Nutrient chapter

Cyclosporine

Species, preparation, dose and limitations are retained on linked claims.

37 recorded mechanisms · 1 availability situations · 4 preserved sources. Draft and verified records are labeled separately.

Read recorded mechanisms Open recursive mind map

The mechanisms

What the sources say this nutrient does, one relationship at a time. Plain wording comes first; the technical statement follows.

The immediate intracellular receptor of cyclosporin A is cyclophilin, a peptidyl-prolyl cis-trans isomerase, and drug binding inhibits that isomerase activity.
Cyclosporine → Human cyclophilin A / PPIA source_derived_draftungraded
Experimental context and source evidence
duration
Not stated here
evidence_access
Primary PubMed abstract and indexed metadata reviewed. Full-text method details not stated here remain unresolved.
experimental_model
Human and mammalian immunophilin biochemistry
exposure
Cyclosporin A
limitations
The report states that inhibition of isomerase activity is not what produces the drug's effect; analysis of cyclosporin-resistant yeast mutants and other isomerase inhibitors pointed to an inhibitory drug-isomerase complex instead. Binding is recorded here without a direction, because binding a protein is not by itself raising or lowering it.
organism
Human and mammalian immunophilin biochemistry
plain_language
The immediate intracellular receptor of cyclosporin A is cyclophilin, a peptidyl-prolyl cis-trans isomerase, and drug binding inhibits that isomerase activity.
primary_references
Nuclear association of a T-cell transcription factor blocked by FK-506 and cyclosporin A. (1991). https://pubmed.ncbi.nlm.nih.gov/1715516/ DOI: 10.1038/352803a0
route
In vitro
tissue
T-lymphocyte signalling
Cyclosporine: the complex that inhibits calcineurin, a second cyclophilin, and the transport step that decides exposure (2026-09-23) · lines 14–14
Original AI-assisted curation of seven primary studies resolved by PubMed title search, with every abstract read and all DOIs cross-checked against live PubMed metadata on 2026-09-23. No reference carries a recorded retraction, erratum or expression of concern. Each of the seven is a separate laboratory and each carries its own lineage key, so none of them can be counted twice as independent support. Study-specific concentrations, kinetic constants and limitations retained. Not publisher full text. · supports · Human and mammalian immunophilin biochemistry · source_derived_draft · unverified_draft
The immediate intracellular receptor of cyclosporin A is cyclophilin, a peptidyl-prolyl cis-trans isomerase, and drug binding inhibits that isomerase activity.
Complete structured claim and evidence
The effects of cyclosporin A are reported to follow from the formation of an inhibitory complex between the drug and its prolyl isomerase, and not from inhibition of the isomerase activity that drug binding also causes.
Cyclosporine → Cyclophilin A-cyclosporine complex source_derived_draftungraded
Experimental context and source evidence
duration
Not stated here
evidence_access
Primary PubMed abstract and indexed metadata reviewed. Full-text method details not stated here remain unresolved.
experimental_model
Mammalian immunophilin biochemistry, with cyclosporin-resistant yeast mutants cited as support
exposure
Cyclosporin A with cyclophilin
limitations
This is the step that makes the drug an inhibitor of anything, and it is why no arrow in this collection runs from cyclosporine to calcineurin directly. The evidence cited for it in this report is the behaviour of other isomerase inhibitors and of cyclosporin-resistant yeast mutants, which is an argument from the pattern of results rather than a measurement of complex formation.
organism
Mammalian immunophilin biochemistry, with cyclosporin-resistant yeast mutants cited as support
plain_language
The effects of cyclosporin A are reported to follow from the formation of an inhibitory complex between the drug and its prolyl isomerase, and not from inhibition of the isomerase activity that drug binding also causes.
primary_references
Nuclear association of a T-cell transcription factor blocked by FK-506 and cyclosporin A. (1991). https://pubmed.ncbi.nlm.nih.gov/1715516/ DOI: 10.1038/352803a0
route
In vitro
tissue
Formation of the drug-immunophilin complex
Cyclosporine: the complex that inhibits calcineurin, a second cyclophilin, and the transport step that decides exposure (2026-09-23) · lines 25–25
Original AI-assisted curation of seven primary studies resolved by PubMed title search, with every abstract read and all DOIs cross-checked against live PubMed metadata on 2026-09-23. No reference carries a recorded retraction, erratum or expression of concern. Each of the seven is a separate laboratory and each carries its own lineage key, so none of them can be counted twice as independent support. Study-specific concentrations, kinetic constants and limitations retained. Not publisher full text. · supports · Mammalian immunophilin biochemistry, with cyclosporin-resistant yeast mutants cited as support · source_derived_draft · unverified_draft
The effects of cyclosporin A are reported to follow from the formation of an inhibitory complex between the drug and its prolyl isomerase, and not from inhibition of the isomerase activity that drug binding also causes.
Complete structured claim and evidence
FK506 likewise acts by forming a drug-dependent complex with FKBP, and it is that complex, not the free drug, that binds and inhibits calcineurin.
Tacrolimus / FK506 → FKBP-FK506 complex source_derived_draftungraded
Experimental context and source evidence
duration
Not stated here
evidence_access
Primary PubMed abstract and indexed metadata reviewed. Full-text method details not stated here remain unresolved.
experimental_model
Purified mammalian proteins
exposure
FK506 (tacrolimus) with FKBP
limitations
Recorded so that the tacrolimus side of this convergence is drawn the same way as the cyclosporine side. The report does not measure the rate or affinity of complex formation itself.
organism
Purified mammalian proteins
plain_language
FK506 likewise acts by forming a drug-dependent complex with FKBP, and it is that complex, not the free drug, that binds and inhibits calcineurin.
primary_references
Calcineurin is a common target of cyclophilin-cyclosporin A and FKBP-FK506 complexes. (1991). https://pubmed.ncbi.nlm.nih.gov/1715244/ DOI: 10.1016/0092-8674(91)90124-h
route
In vitro
tissue
Formation of the drug-immunophilin complex
Cyclosporine: the complex that inhibits calcineurin, a second cyclophilin, and the transport step that decides exposure (2026-09-23) · lines 36–36
Original AI-assisted curation of seven primary studies resolved by PubMed title search, with every abstract read and all DOIs cross-checked against live PubMed metadata on 2026-09-23. No reference carries a recorded retraction, erratum or expression of concern. Each of the seven is a separate laboratory and each carries its own lineage key, so none of them can be counted twice as independent support. Study-specific concentrations, kinetic constants and limitations retained. Not publisher full text. · supports · Purified mammalian proteins · source_derived_draft · unverified_draft
FK506 likewise acts by forming a drug-dependent complex with FKBP, and it is that complex, not the free drug, that binds and inhibits calcineurin.
Complete structured claim and evidence
The cyclophilin-cyclosporin A complex competitively binds and inhibits the calcium- and calmodulin-dependent phosphatase calcineurin.
Cyclophilin A-cyclosporine complex → Calcineurin source_derived_draftungraded
Experimental context and source evidence
duration
Not stated here
evidence_access
Primary PubMed abstract and indexed metadata reviewed. Full-text method details not stated here remain unresolved.
experimental_model
Purified mammalian proteins
exposure
Cyclophilin complexed with cyclosporin A
limitations
Binding and inhibition of calcineurin did not require calmodulin in this report. The inhibitor is the complex, not the drug, so this arrow must not be redrawn from cyclosporine directly to calcineurin.
organism
Purified mammalian proteins
plain_language
The cyclophilin-cyclosporin A complex competitively binds and inhibits the calcium- and calmodulin-dependent phosphatase calcineurin.
primary_references
Calcineurin is a common target of cyclophilin-cyclosporin A and FKBP-FK506 complexes. (1991). https://pubmed.ncbi.nlm.nih.gov/1715244/ DOI: 10.1016/0092-8674(91)90124-h
route
In vitro
tissue
Calcineurin phosphatase activity
Cyclosporine: the complex that inhibits calcineurin, a second cyclophilin, and the transport step that decides exposure (2026-09-23) · lines 47–47
Original AI-assisted curation of seven primary studies resolved by PubMed title search, with every abstract read and all DOIs cross-checked against live PubMed metadata on 2026-09-23. No reference carries a recorded retraction, erratum or expression of concern. Each of the seven is a separate laboratory and each carries its own lineage key, so none of them can be counted twice as independent support. Study-specific concentrations, kinetic constants and limitations retained. Not publisher full text. · supports · Purified mammalian proteins · source_derived_draft · unverified_draft
The cyclophilin-cyclosporin A complex competitively binds and inhibits the calcium- and calmodulin-dependent phosphatase calcineurin.
Complete structured claim and evidence
Cyclophilin without cyclosporin A bound did not bind or inhibit calcineurin, and neither did FKBP alone, FKBP with rapamycin, or FKBP with the inactive analogue 506BD.
Human cyclophilin A / PPIA → Calcineurin source_derived_draftungraded
Experimental context and source evidence
duration
Not stated here
evidence_access
Primary PubMed abstract and indexed metadata reviewed. Full-text method details not stated here remain unresolved.
experimental_model
Purified mammalian proteins
exposure
Free cyclophilin; free FKBP; FKBP-rapamycin; FKBP-506BD
limitations
This is the control set that makes the complex the active species. It is recorded as a measured null rather than as an absence of evidence.
organism
Purified mammalian proteins
plain_language
Cyclophilin without cyclosporin A bound did not bind or inhibit calcineurin, and neither did FKBP alone, FKBP with rapamycin, or FKBP with the inactive analogue 506BD.
primary_references
Calcineurin is a common target of cyclophilin-cyclosporin A and FKBP-FK506 complexes. (1991). https://pubmed.ncbi.nlm.nih.gov/1715244/ DOI: 10.1016/0092-8674(91)90124-h
route
In vitro
tissue
Calcineurin phosphatase activity
Cyclosporine: the complex that inhibits calcineurin, a second cyclophilin, and the transport step that decides exposure (2026-09-23) · lines 58–58
Original AI-assisted curation of seven primary studies resolved by PubMed title search, with every abstract read and all DOIs cross-checked against live PubMed metadata on 2026-09-23. No reference carries a recorded retraction, erratum or expression of concern. Each of the seven is a separate laboratory and each carries its own lineage key, so none of them can be counted twice as independent support. Study-specific concentrations, kinetic constants and limitations retained. Not publisher full text. · supports · Purified mammalian proteins · source_derived_draft · unverified_draft
Cyclophilin without cyclosporin A bound did not bind or inhibit calcineurin, and neither did FKBP alone, FKBP with rapamycin, or FKBP with the inactive analogue 506BD.
Complete structured claim and evidence
The FKBP-FK506 complex also competitively binds and inhibits calcineurin, making calcineurin the common target of two structurally unrelated immunophilin-drug complexes.
FKBP-FK506 complex → Calcineurin source_derived_draftungraded
Experimental context and source evidence
duration
Not stated here
evidence_access
Primary PubMed abstract and indexed metadata reviewed. Full-text method details not stated here remain unresolved.
experimental_model
Purified mammalian proteins
exposure
FKBP complexed with FK506 (tacrolimus)
limitations
Convergence on one target does not make the two drugs interchangeable; their immunophilins, their tissue distribution and their other complexes differ, and none of that is measured here.
organism
Purified mammalian proteins
plain_language
The FKBP-FK506 complex also competitively binds and inhibits calcineurin, making calcineurin the common target of two structurally unrelated immunophilin-drug complexes.
primary_references
Calcineurin is a common target of cyclophilin-cyclosporin A and FKBP-FK506 complexes. (1991). https://pubmed.ncbi.nlm.nih.gov/1715244/ DOI: 10.1016/0092-8674(91)90124-h
route
In vitro
tissue
Calcineurin phosphatase activity
Cyclosporine: the complex that inhibits calcineurin, a second cyclophilin, and the transport step that decides exposure (2026-09-23) · lines 69–69
Original AI-assisted curation of seven primary studies resolved by PubMed title search, with every abstract read and all DOIs cross-checked against live PubMed metadata on 2026-09-23. No reference carries a recorded retraction, erratum or expression of concern. Each of the seven is a separate laboratory and each carries its own lineage key, so none of them can be counted twice as independent support. Study-specific concentrations, kinetic constants and limitations retained. Not publisher full text. · supports · Purified mammalian proteins · source_derived_draft · unverified_draft
The FKBP-FK506 complex also competitively binds and inhibits calcineurin, making calcineurin the common target of two structurally unrelated immunophilin-drug complexes.
Complete structured claim and evidence
FK506 acts through a drug-dependent complex with FKBP, its own immediate immunophilin receptor, rather than through the free drug.
Tacrolimus / FK506 → FKBP12 / FKBP1A source_derived_draftungraded
Experimental context and source evidence
duration
Not stated here
evidence_access
Primary PubMed abstract and indexed metadata reviewed. Full-text method details not stated here remain unresolved.
experimental_model
Mammalian immunophilin biochemistry
exposure
FK506 (tacrolimus)
limitations
Recorded so that the tacrolimus arm of this convergence is not attributed to the free drug either. Binding carries no direction.
organism
Mammalian immunophilin biochemistry
plain_language
FK506 acts through a drug-dependent complex with FKBP, its own immediate immunophilin receptor, rather than through the free drug.
primary_references
Calcineurin is a common target of cyclophilin-cyclosporin A and FKBP-FK506 complexes. (1991). https://pubmed.ncbi.nlm.nih.gov/1715244/ DOI: 10.1016/0092-8674(91)90124-h
route
In vitro
tissue
T-lymphocyte signalling
Cyclosporine: the complex that inhibits calcineurin, a second cyclophilin, and the transport step that decides exposure (2026-09-23) · lines 80–80
Original AI-assisted curation of seven primary studies resolved by PubMed title search, with every abstract read and all DOIs cross-checked against live PubMed metadata on 2026-09-23. No reference carries a recorded retraction, erratum or expression of concern. Each of the seven is a separate laboratory and each carries its own lineage key, so none of them can be counted twice as independent support. Study-specific concentrations, kinetic constants and limitations retained. Not publisher full text. · supports · Mammalian immunophilin biochemistry · source_derived_draft · unverified_draft
FK506 acts through a drug-dependent complex with FKBP, its own immediate immunophilin receptor, rather than through the free drug.
Complete structured claim and evidence
In the 2.8-angstrom crystal structure the cyclophilin A-cyclosporin A complex binds a composite surface formed by the catalytic and regulatory subunits of calcineurin, and unlike FKBP-FK506 it also interacts with Arg-122 at the calcineurin active site.
Cyclophilin A-cyclosporine complex → Calcineurin source_derived_draftungraded
Experimental context and source evidence
duration
Not applicable
evidence_access
Primary PubMed abstract and indexed metadata reviewed. Full-text method details not stated here remain unresolved.
experimental_model
Recombinant human proteins in crystal
exposure
Cyclophilin A with cyclosporin A bound
limitations
A structure shows contact, not rate. The authors read the active-site contact as implying direct involvement in regulating catalysis, which is an interpretation and is recorded as one. No direction is recorded for this claim, because a binding geometry is not itself an increase or a decrease.
organism
Recombinant human proteins in crystal
plain_language
In the 2.8-angstrom crystal structure the cyclophilin A-cyclosporin A complex binds a composite surface formed by the catalytic and regulatory subunits of calcineurin, and unlike FKBP-FK506 it also interacts with Arg-122 at the calcineurin active site.
primary_references
Crystal structure of calcineurin-cyclophilin-cyclosporin shows common but distinct recognition of immunophilin-drug complexes. (2002). https://pubmed.ncbi.nlm.nih.gov/12218175/ DOI: 10.1073/pnas.192206699
route
In vitro
tissue
Calcineurin catalytic and regulatory subunit interface
Cyclosporine: the complex that inhibits calcineurin, a second cyclophilin, and the transport step that decides exposure (2026-09-23) · lines 91–91
Original AI-assisted curation of seven primary studies resolved by PubMed title search, with every abstract read and all DOIs cross-checked against live PubMed metadata on 2026-09-23. No reference carries a recorded retraction, erratum or expression of concern. Each of the seven is a separate laboratory and each carries its own lineage key, so none of them can be counted twice as independent support. Study-specific concentrations, kinetic constants and limitations retained. Not publisher full text. · supports · Recombinant human proteins in crystal · source_derived_draft · unverified_draft
In the 2.8-angstrom crystal structure the cyclophilin A-cyclosporin A complex binds a composite surface formed by the catalytic and regulatory subunits of calcineurin, and unlike FKBP-FK506 it also interacts with Arg-122 at the calcineurin active site.
Complete structured claim and evidence
NFAT is assembled when an antigen-receptor signal drives a pre-existing cytoplasmic subunit into the nucleus to join a newly synthesised nuclear subunit, and cyclosporin A blocks translocation of the cytoplasmic component.
Cyclosporine → NFAT cytoplasmic subunit nuclear translocation source_derived_draftungraded
Experimental context and source evidence
duration
Not stated here
evidence_access
Primary PubMed abstract and indexed metadata reviewed. Full-text method details not stated here remain unresolved.
experimental_model
T lymphocytes
exposure
Cyclosporin A; FK506 compared alongside
limitations
Synthesis of the nuclear subunit was not affected, so the block is on translocation rather than on making the factor. The abstract does not give concentrations or a time course.
organism
T lymphocytes
plain_language
NFAT is assembled when an antigen-receptor signal drives a pre-existing cytoplasmic subunit into the nucleus to join a newly synthesised nuclear subunit, and cyclosporin A blocks translocation of the cytoplasmic component.
primary_references
Nuclear association of a T-cell transcription factor blocked by FK-506 and cyclosporin A. (1991). https://pubmed.ncbi.nlm.nih.gov/1715516/ DOI: 10.1038/352803a0
route
In vitro
tissue
Antigen-receptor signalling to cytokine genes
Cyclosporine: the complex that inhibits calcineurin, a second cyclophilin, and the transport step that decides exposure (2026-09-23) · lines 102–102
Original AI-assisted curation of seven primary studies resolved by PubMed title search, with every abstract read and all DOIs cross-checked against live PubMed metadata on 2026-09-23. No reference carries a recorded retraction, erratum or expression of concern. Each of the seven is a separate laboratory and each carries its own lineage key, so none of them can be counted twice as independent support. Study-specific concentrations, kinetic constants and limitations retained. Not publisher full text. · supports · T lymphocytes · source_derived_draft · unverified_draft
NFAT is assembled when an antigen-receptor signal drives a pre-existing cytoplasmic subunit into the nucleus to join a newly synthesised nuclear subunit, and cyclosporin A blocks translocation of the cytoplasmic component.
Complete structured claim and evidence
Transcription directed by NFAT is blocked in T cells treated with cyclosporin A, which is why the drug reaches the cytokine genes that coordinate the immune response.
Cyclosporine → IL2 transcription source_derived_draftungraded
Experimental context and source evidence
duration
Not stated here
evidence_access
Primary PubMed abstract and indexed metadata reviewed. Full-text method details not stated here remain unresolved.
experimental_model
T lymphocytes
exposure
Cyclosporin A
limitations
The same report records little or no effect on other transcription factors such as AP-1 and NF-kappa B, so this is selectivity for the NFAT route rather than general transcriptional shutdown. AP-1 and NF-kappa B are not recorded as separate entities here because the abstract reports them only as unaffected comparators.
organism
T lymphocytes
plain_language
Transcription directed by NFAT is blocked in T cells treated with cyclosporin A, which is why the drug reaches the cytokine genes that coordinate the immune response.
primary_references
Nuclear association of a T-cell transcription factor blocked by FK-506 and cyclosporin A. (1991). https://pubmed.ncbi.nlm.nih.gov/1715516/ DOI: 10.1038/352803a0
route
In vitro
tissue
Cytokine gene transcription
Cyclosporine: the complex that inhibits calcineurin, a second cyclophilin, and the transport step that decides exposure (2026-09-23) · lines 113–113
Original AI-assisted curation of seven primary studies resolved by PubMed title search, with every abstract read and all DOIs cross-checked against live PubMed metadata on 2026-09-23. No reference carries a recorded retraction, erratum or expression of concern. Each of the seven is a separate laboratory and each carries its own lineage key, so none of them can be counted twice as independent support. Study-specific concentrations, kinetic constants and limitations retained. Not publisher full text. · supports · T lymphocytes · source_derived_draft · unverified_draft
Transcription directed by NFAT is blocked in T cells treated with cyclosporin A, which is why the drug reaches the cytokine genes that coordinate the immune response.
Complete structured claim and evidence
Liver and heart mitochondrial matrix fractions, prepared free of membrane and cytosolic contamination, contain cyclosporin-sensitive peptidyl-prolyl cis-trans isomerase, titrated at 110.6 plus or minus 10.1 and 165.4 plus or minus 15.0 picomoles of enzyme per milligram of protein with a Ki of about 2.5 nanomolar.
Cyclosporine → Cyclosporin-sensitive mitochondrial matrix peptidyl-prolyl isomerase, 1990 titration source_derived_draftungraded
Experimental context and source evidence
duration
Not stated here
evidence_access
Primary PubMed abstract and indexed metadata reviewed. Full-text method details not stated here remain unresolved.
experimental_model
Rat liver and heart mitochondria
exposure
Cyclosporin A titration
limitations
This is a different cyclophilin from the cytosolic one that carries the immunosuppressive mechanism, and the two must not be merged. The 1990 report identifies a matrix isomerase by activity and binding site number; the gene assignment to Ppif came later and is not part of this measurement.
organism
Rat liver and heart mitochondria
plain_language
Liver and heart mitochondrial matrix fractions, prepared free of membrane and cytosolic contamination, contain cyclosporin-sensitive peptidyl-prolyl cis-trans isomerase, titrated at 110.6 plus or minus 10.1 and 165.4 plus or minus 15.0 picomoles of enzyme per milligram of protein with a Ki of about 2.5 nanomolar.
primary_references
Inhibition of Ca2+-induced large-amplitude swelling of liver and heart mitochondria by cyclosporin is probably caused by the inhibitor binding to mitochondrial-matrix peptidyl-prolyl cis-trans isomerase and preventing it interacting with the adenine nucleotide translocase. (1990). https://pubmed.ncbi.nlm.nih.gov/2160810/ DOI: 10.1042/bj2680153
route
In vitro
tissue
Mitochondrial matrix peptidyl-prolyl isomerase
Cyclosporine: the complex that inhibits calcineurin, a second cyclophilin, and the transport step that decides exposure (2026-09-23) · lines 124–124
Original AI-assisted curation of seven primary studies resolved by PubMed title search, with every abstract read and all DOIs cross-checked against live PubMed metadata on 2026-09-23. No reference carries a recorded retraction, erratum or expression of concern. Each of the seven is a separate laboratory and each carries its own lineage key, so none of them can be counted twice as independent support. Study-specific concentrations, kinetic constants and limitations retained. Not publisher full text. · supports · Rat liver and heart mitochondria · source_derived_draft · unverified_draft
Liver and heart mitochondrial matrix fractions, prepared free of membrane and cytosolic contamination, contain cyclosporin-sensitive peptidyl-prolyl cis-trans isomerase, titrated at 110.6 plus or minus 10.1 and 165.4 plus or minus 15.0 picomoles of enzyme per milligram of protein with a Ki of about 2.5 nanomolar.
Complete structured claim and evidence
Cyclosporin A inhibited the large-amplitude swelling that isolated rat liver and heart mitochondria show when exposed to 250 micromolar calcium, with the number of cyclosporin-binding sites titrated at 113.7 plus or minus 5.0 and 124.3 plus or minus 11.2 picomoles per milligram of protein and a Ki of about 5 nanomolar.
Cyclosporine → Mitochondrial permeability transition source_derived_draftungraded
Experimental context and source evidence
duration
Not stated here
evidence_access
Primary PubMed abstract and indexed metadata reviewed. Full-text method details not stated here remain unresolved.
experimental_model
Rat liver and heart mitochondria
exposure
Cyclosporin A, titrated
limitations
Isolated mitochondria under respiratory-chain inhibition in KSCN or sucrose medium, with 250 micromolar calcium, which is a supraphysiological calcium load in a stripped system. Bongkrekic acid inhibited swelling in both media and ADP inhibited it in KSCN medium with the effect reversed by carboxyatractyloside, so the adenine nucleotide carrier is implicated alongside the isomerase. The proposed interaction between the two is the authors' model, not a measurement.
organism
Rat liver and heart mitochondria
plain_language
Cyclosporin A inhibited the large-amplitude swelling that isolated rat liver and heart mitochondria show when exposed to 250 micromolar calcium, with the number of cyclosporin-binding sites titrated at 113.7 plus or minus 5.0 and 124.3 plus or minus 11.2 picomoles per milligram of protein and a Ki of about 5 nanomolar.
primary_references
Inhibition of Ca2+-induced large-amplitude swelling of liver and heart mitochondria by cyclosporin is probably caused by the inhibitor binding to mitochondrial-matrix peptidyl-prolyl cis-trans isomerase and preventing it interacting with the adenine nucleotide translocase. (1990). https://pubmed.ncbi.nlm.nih.gov/2160810/ DOI: 10.1042/bj2680153
route
In vitro
tissue
Calcium-induced inner-membrane pore opening
Cyclosporine: the complex that inhibits calcineurin, a second cyclophilin, and the transport step that decides exposure (2026-09-23) · lines 135–135
Original AI-assisted curation of seven primary studies resolved by PubMed title search, with every abstract read and all DOIs cross-checked against live PubMed metadata on 2026-09-23. No reference carries a recorded retraction, erratum or expression of concern. Each of the seven is a separate laboratory and each carries its own lineage key, so none of them can be counted twice as independent support. Study-specific concentrations, kinetic constants and limitations retained. Not publisher full text. · supports · Rat liver and heart mitochondria · source_derived_draft · unverified_draft
Cyclosporin A inhibited the large-amplitude swelling that isolated rat liver and heart mitochondria show when exposed to 250 micromolar calcium, with the number of cyclosporin-binding sites titrated at 113.7 plus or minus 5.0 and 124.3 plus or minus 11.2 picomoles per milligram of protein and a Ki of about 5 nanomolar.
Complete structured claim and evidence
Cyclosporin A inhibited OATP2-mediated uptake of labelled cerivastatin in transporter-expressing MDCKII cells with a Ki of 0.2 micromolar.
Cyclosporine → Human OATP1B1 / SLCO1B1 source_derived_draftungraded
Experimental context and source evidence
duration
Not stated here
evidence_access
Primary PubMed abstract and indexed metadata reviewed. Full-text method details not stated here remain unresolved.
experimental_model
Human OATP2 (OATP1B1 / SLCO1B1) expressed in MDCKII cells
exposure
Cyclosporin A
limitations
The transporter is named OATP2 in this 2003 report, which is the protein now called OATP1B1 and encoded by SLCO1B1; the same entity is reused here rather than forked. The Ki is for cerivastatin as the probe substrate and does not transfer unchanged to other OATP1B1 substrates.
organism
Human OATP2 (OATP1B1 / SLCO1B1) expressed in MDCKII cells
plain_language
Cyclosporin A inhibited OATP2-mediated uptake of labelled cerivastatin in transporter-expressing MDCKII cells with a Ki of 0.2 micromolar.
primary_references
Inhibition of transporter-mediated hepatic uptake as a mechanism for drug-drug interaction between cerivastatin and cyclosporin A. (2003). https://pubmed.ncbi.nlm.nih.gov/12538813/ DOI: 10.1124/jpet.102.041921
route
In vitro
tissue
Hepatic sinusoidal uptake transport
Cyclosporine: the complex that inhibits calcineurin, a second cyclophilin, and the transport step that decides exposure (2026-09-23) · lines 146–146
Original AI-assisted curation of seven primary studies resolved by PubMed title search, with every abstract read and all DOIs cross-checked against live PubMed metadata on 2026-09-23. No reference carries a recorded retraction, erratum or expression of concern. Each of the seven is a separate laboratory and each carries its own lineage key, so none of them can be counted twice as independent support. Study-specific concentrations, kinetic constants and limitations retained. Not publisher full text. · supports · Human OATP2 (OATP1B1 / SLCO1B1) expressed in MDCKII cells · source_derived_draft · unverified_draft
Cyclosporin A inhibited OATP2-mediated uptake of labelled cerivastatin in transporter-expressing MDCKII cells with a Ki of 0.2 micromolar.
Complete structured claim and evidence
Uptake of labelled cerivastatin into human hepatocytes from three donors was inhibited by cyclosporin A with Ki values of 0.3 to 0.7 micromolar, against Km values for the uptake itself of 3 to 18 micromolar, so more than 70 per cent of total uptake at therapeutic concentrations was carrier-mediated.
Cyclosporine → Cerivastatin source_derived_draftungraded
Experimental context and source evidence
duration
Not stated here
evidence_access
Primary PubMed abstract and indexed metadata reviewed. Full-text method details not stated here remain unresolved.
experimental_model
Human hepatocytes from three donors
exposure
Cyclosporin A
limitations
The pool that falls is the hepatocyte interior. Plasma exposure is expected to move the other way and was not measured here. Three donors is a small panel for a kinetic range.
organism
Human hepatocytes from three donors
plain_language
Uptake of labelled cerivastatin into human hepatocytes from three donors was inhibited by cyclosporin A with Ki values of 0.3 to 0.7 micromolar, against Km values for the uptake itself of 3 to 18 micromolar, so more than 70 per cent of total uptake at therapeutic concentrations was carrier-mediated.
primary_references
Inhibition of transporter-mediated hepatic uptake as a mechanism for drug-drug interaction between cerivastatin and cyclosporin A. (2003). https://pubmed.ncbi.nlm.nih.gov/12538813/ DOI: 10.1124/jpet.102.041921
route
In vitro
tissue
Hepatocyte interior
Cyclosporine: the complex that inhibits calcineurin, a second cyclophilin, and the transport step that decides exposure (2026-09-23) · lines 157–157
Original AI-assisted curation of seven primary studies resolved by PubMed title search, with every abstract read and all DOIs cross-checked against live PubMed metadata on 2026-09-23. No reference carries a recorded retraction, erratum or expression of concern. Each of the seven is a separate laboratory and each carries its own lineage key, so none of them can be counted twice as independent support. Study-specific concentrations, kinetic constants and limitations retained. Not publisher full text. · supports · Human hepatocytes from three donors · source_derived_draft · unverified_draft
Uptake of labelled cerivastatin into human hepatocytes from three donors was inhibited by cyclosporin A with Ki values of 0.3 to 0.7 micromolar, against Km values for the uptake itself of 3 to 18 micromolar, so more than 70 per cent of total uptake at therapeutic concentrations was carrier-mediated.
Complete structured claim and evidence
Cyclosporin A inhibited the in vitro metabolism of labelled cerivastatin only at concentrations above 30 micromolar, two orders of magnitude above the concentrations that inhibited its transport.
Cyclosporine → Cerivastatin source_derived_draftungraded
Experimental context and source evidence
duration
Not stated here
evidence_access
Primary PubMed abstract and indexed metadata reviewed. Full-text method details not stated here remain unresolved.
experimental_model
In vitro cerivastatin metabolism
exposure
Cyclosporin A
limitations
Recorded as the measured null that separates the two candidate mechanisms for this interaction. The authors conclude the interaction is mainly transporter inhibition, which is an interpretation of these two numbers rather than a separate measurement.
organism
In vitro cerivastatin metabolism
plain_language
Cyclosporin A inhibited the in vitro metabolism of labelled cerivastatin only at concentrations above 30 micromolar, two orders of magnitude above the concentrations that inhibited its transport.
primary_references
Inhibition of transporter-mediated hepatic uptake as a mechanism for drug-drug interaction between cerivastatin and cyclosporin A. (2003). https://pubmed.ncbi.nlm.nih.gov/12538813/ DOI: 10.1124/jpet.102.041921
route
In vitro
tissue
Drug metabolism
Cyclosporine: the complex that inhibits calcineurin, a second cyclophilin, and the transport step that decides exposure (2026-09-23) · lines 168–168
Original AI-assisted curation of seven primary studies resolved by PubMed title search, with every abstract read and all DOIs cross-checked against live PubMed metadata on 2026-09-23. No reference carries a recorded retraction, erratum or expression of concern. Each of the seven is a separate laboratory and each carries its own lineage key, so none of them can be counted twice as independent support. Study-specific concentrations, kinetic constants and limitations retained. Not publisher full text. · supports · In vitro cerivastatin metabolism · source_derived_draft · unverified_draft
Cyclosporin A inhibited the in vitro metabolism of labelled cerivastatin only at concentrations above 30 micromolar, two orders of magnitude above the concentrations that inhibited its transport.
Complete structured claim and evidence
Heterologously expressed CYP3A4 produced three primary cyclosporine metabolites, AM1, AM9 and AM4N, with substrate inhibition observed for AM1 and AM9 formation.
Human cytochrome P450 3A4 → Cyclosporine source_derived_draftungraded
Experimental context and source evidence
duration
Not stated here
evidence_access
Primary PubMed abstract and indexed metadata reviewed. Full-text method details not stated here remain unresolved.
experimental_model
Heterologously expressed human CYP3A4
exposure
Cyclosporin A
limitations
Substrate inhibition means the rate does not rise linearly with concentration, so a single-point rate from this system does not scale. The step consumes the parent drug, which is the direction recorded.
organism
Heterologously expressed human CYP3A4
plain_language
Heterologously expressed CYP3A4 produced three primary cyclosporine metabolites, AM1, AM9 and AM4N, with substrate inhibition observed for AM1 and AM9 formation.
primary_references
In vitro metabolism of cyclosporine A by human kidney CYP3A5. (2004). https://pubmed.ncbi.nlm.nih.gov/15450954/ DOI: 10.1016/j.bcp.2004.07.012
route
In vitro
tissue
Oxidative drug metabolism
Cyclosporine: the complex that inhibits calcineurin, a second cyclophilin, and the transport step that decides exposure (2026-09-23) · lines 179–179
Original AI-assisted curation of seven primary studies resolved by PubMed title search, with every abstract read and all DOIs cross-checked against live PubMed metadata on 2026-09-23. No reference carries a recorded retraction, erratum or expression of concern. Each of the seven is a separate laboratory and each carries its own lineage key, so none of them can be counted twice as independent support. Study-specific concentrations, kinetic constants and limitations retained. Not publisher full text. · supports · Heterologously expressed human CYP3A4 · source_derived_draft · unverified_draft
Heterologously expressed CYP3A4 produced three primary cyclosporine metabolites, AM1, AM9 and AM4N, with substrate inhibition observed for AM1 and AM9 formation.
Complete structured claim and evidence
CYP3A5 formed only AM9 from cyclosporine, not AM1 or AM4N, with substrate inhibition and an apparent Km of 11.3 micromolar.
Human cytochrome P450 3A5 → Cyclosporine metabolite AM9 source_derived_draftungraded
Experimental context and source evidence
duration
Not stated here
evidence_access
Primary PubMed abstract and indexed metadata reviewed. Full-text method details not stated here remain unresolved.
experimental_model
Heterologously expressed human CYP3A5
exposure
Cyclosporin A
limitations
A narrower product range than CYP3A4 in the same comparison. Recorded as the enzyme raising one named metabolite, with the two metabolites it did not form recorded as a null in the companion claim.
organism
Heterologously expressed human CYP3A5
plain_language
CYP3A5 formed only AM9 from cyclosporine, not AM1 or AM4N, with substrate inhibition and an apparent Km of 11.3 micromolar.
primary_references
In vitro metabolism of cyclosporine A by human kidney CYP3A5. (2004). https://pubmed.ncbi.nlm.nih.gov/15450954/ DOI: 10.1016/j.bcp.2004.07.012
route
In vitro
tissue
Oxidative drug metabolism
Cyclosporine: the complex that inhibits calcineurin, a second cyclophilin, and the transport step that decides exposure (2026-09-23) · lines 190–190
Original AI-assisted curation of seven primary studies resolved by PubMed title search, with every abstract read and all DOIs cross-checked against live PubMed metadata on 2026-09-23. No reference carries a recorded retraction, erratum or expression of concern. Each of the seven is a separate laboratory and each carries its own lineage key, so none of them can be counted twice as independent support. Study-specific concentrations, kinetic constants and limitations retained. Not publisher full text. · supports · Heterologously expressed human CYP3A5 · source_derived_draft · unverified_draft
CYP3A5 formed only AM9 from cyclosporine, not AM1 or AM4N, with substrate inhibition and an apparent Km of 11.3 micromolar.
Complete structured claim and evidence
CYP3A5 did not form AM1 from cyclosporine in the same comparison in which CYP3A4 did.
Human cytochrome P450 3A5 → Cyclosporine metabolite AM1 source_derived_draftungraded
Experimental context and source evidence
duration
Not stated here
evidence_access
Primary PubMed abstract and indexed metadata reviewed. Full-text method details not stated here remain unresolved.
experimental_model
Heterologously expressed human CYP3A4 and CYP3A5
exposure
Cyclosporin A
limitations
A measured absence in one recombinant system, not a statement that the reaction is impossible in tissue.
organism
Heterologously expressed human CYP3A4 and CYP3A5
plain_language
CYP3A5 did not form AM1 from cyclosporine in the same comparison in which CYP3A4 did.
primary_references
In vitro metabolism of cyclosporine A by human kidney CYP3A5. (2004). https://pubmed.ncbi.nlm.nih.gov/15450954/ DOI: 10.1016/j.bcp.2004.07.012
route
In vitro
tissue
Oxidative drug metabolism
Cyclosporine: the complex that inhibits calcineurin, a second cyclophilin, and the transport step that decides exposure (2026-09-23) · lines 201–201
Original AI-assisted curation of seven primary studies resolved by PubMed title search, with every abstract read and all DOIs cross-checked against live PubMed metadata on 2026-09-23. No reference carries a recorded retraction, erratum or expression of concern. Each of the seven is a separate laboratory and each carries its own lineage key, so none of them can be counted twice as independent support. Study-specific concentrations, kinetic constants and limitations retained. Not publisher full text. · supports · Heterologously expressed human CYP3A4 and CYP3A5 · source_derived_draft · unverified_draft
CYP3A5 did not form AM1 from cyclosporine in the same comparison in which CYP3A4 did.
Complete structured claim and evidence
Microsomes from human kidney produced only AM9, and the rate of formation at 2 and 20 micromolar cyclosporine was positively associated with detectable CYP3A5 protein and with the CYP3A5*1 allele in 4 of the 20 kidneys tested.
Human kidney microsomal CYP3A activity, twenty-donor panel → Cyclosporine metabolite AM9 source_derived_draftungraded
Experimental context and source evidence
duration
Not stated here
evidence_access
Primary PubMed abstract and indexed metadata reviewed. Full-text method details not stated here remain unresolved.
experimental_model
Human kidney microsomes from twenty donors
exposure
Cyclosporin A at 2 and 20 micromolar
limitations
Four of twenty kidneys carried the allele, so the genotype comparison rests on a small group. Ketoconazole at 200 nanomolar inhibited renal AM9 formation by 22 to 55 per cent across 2 to 45 micromolar cyclosporine, which supports a CYP3A route without isolating CYP3A5 from CYP3A4 pharmacologically.
organism
Human kidney microsomes from twenty donors
plain_language
Microsomes from human kidney produced only AM9, and the rate of formation at 2 and 20 micromolar cyclosporine was positively associated with detectable CYP3A5 protein and with the CYP3A5*1 allele in 4 of the 20 kidneys tested.
primary_references
In vitro metabolism of cyclosporine A by human kidney CYP3A5. (2004). https://pubmed.ncbi.nlm.nih.gov/15450954/ DOI: 10.1016/j.bcp.2004.07.012
route
In vitro
tissue
Renal drug metabolism
Cyclosporine: the complex that inhibits calcineurin, a second cyclophilin, and the transport step that decides exposure (2026-09-23) · lines 212–212
Original AI-assisted curation of seven primary studies resolved by PubMed title search, with every abstract read and all DOIs cross-checked against live PubMed metadata on 2026-09-23. No reference carries a recorded retraction, erratum or expression of concern. Each of the seven is a separate laboratory and each carries its own lineage key, so none of them can be counted twice as independent support. Study-specific concentrations, kinetic constants and limitations retained. Not publisher full text. · supports · Human kidney microsomes from twenty donors · source_derived_draft · unverified_draft
Microsomes from human kidney produced only AM9, and the rate of formation at 2 and 20 micromolar cyclosporine was positively associated with detectable CYP3A5 protein and with the CYP3A5*1 allele in 4 of the 20 kidneys tested.
Complete structured claim and evidence
Cyclosporine significantly decreased renal expression of the magnesium channel TRPM6 in a rat model of cyclosporine nephrotoxicity.
Cyclosporine → Rat TRPM6 source_derived_draftungraded
Experimental context and source evidence
duration
Not stated here
evidence_access
Primary PubMed abstract and indexed metadata reviewed. Full-text method details not stated here remain unresolved.
experimental_model
Rat model of cyclosporine nephrotoxicity
exposure
Cyclosporine, dose and duration not stated here
limitations
Rat expression data. The authors read this as the molecular basis of the renal magnesium loss seen in people given cyclosporine, which is a cross-species interpretation and is recorded as one. Expression is not the same as channel activity.
organism
Rat model of cyclosporine nephrotoxicity
plain_language
Cyclosporine significantly decreased renal expression of the magnesium channel TRPM6 in a rat model of cyclosporine nephrotoxicity.
primary_references
Expression of renal distal tubule transporters TRPM6 and NCC in a rat model of cyclosporine nephrotoxicity and effect of EGF treatment. (2011). https://pubmed.ncbi.nlm.nih.gov/21653632/ DOI: 10.1152/ajprenal.00116.2011
route
In vivo
tissue
Distal convoluted tubule
Cyclosporine: the complex that inhibits calcineurin, a second cyclophilin, and the transport step that decides exposure (2026-09-23) · lines 223–223
Original AI-assisted curation of seven primary studies resolved by PubMed title search, with every abstract read and all DOIs cross-checked against live PubMed metadata on 2026-09-23. No reference carries a recorded retraction, erratum or expression of concern. Each of the seven is a separate laboratory and each carries its own lineage key, so none of them can be counted twice as independent support. Study-specific concentrations, kinetic constants and limitations retained. Not publisher full text. · supports · Rat model of cyclosporine nephrotoxicity · source_derived_draft · unverified_draft
Cyclosporine significantly decreased renal expression of the magnesium channel TRPM6 in a rat model of cyclosporine nephrotoxicity.
Complete structured claim and evidence
Cyclosporine significantly decreased renal expression of TRPM7 alongside TRPM6 in the same rat model.
Cyclosporine → Rat TRPM7 source_derived_draftungraded
Experimental context and source evidence
duration
Not stated here
evidence_access
Primary PubMed abstract and indexed metadata reviewed. Full-text method details not stated here remain unresolved.
experimental_model
Rat model of cyclosporine nephrotoxicity
exposure
Cyclosporine, dose and duration not stated here
limitations
Rat expression data, reported together with TRPM6 without separating their contributions to the magnesium loss.
organism
Rat model of cyclosporine nephrotoxicity
plain_language
Cyclosporine significantly decreased renal expression of TRPM7 alongside TRPM6 in the same rat model.
primary_references
Expression of renal distal tubule transporters TRPM6 and NCC in a rat model of cyclosporine nephrotoxicity and effect of EGF treatment. (2011). https://pubmed.ncbi.nlm.nih.gov/21653632/ DOI: 10.1152/ajprenal.00116.2011
route
In vivo
tissue
Kidney
Cyclosporine: the complex that inhibits calcineurin, a second cyclophilin, and the transport step that decides exposure (2026-09-23) · lines 234–234
Original AI-assisted curation of seven primary studies resolved by PubMed title search, with every abstract read and all DOIs cross-checked against live PubMed metadata on 2026-09-23. No reference carries a recorded retraction, erratum or expression of concern. Each of the seven is a separate laboratory and each carries its own lineage key, so none of them can be counted twice as independent support. Study-specific concentrations, kinetic constants and limitations retained. Not publisher full text. · supports · Rat model of cyclosporine nephrotoxicity · source_derived_draft · unverified_draft
Cyclosporine significantly decreased renal expression of TRPM7 alongside TRPM6 in the same rat model.
Complete structured claim and evidence
Cyclosporine significantly decreased renal expression of epidermal growth factor in the same rat model.
Cyclosporine → Rat epidermal growth factor source_derived_draftungraded
Experimental context and source evidence
duration
Not stated here
evidence_access
Primary PubMed abstract and indexed metadata reviewed. Full-text method details not stated here remain unresolved.
experimental_model
Rat model of cyclosporine nephrotoxicity
exposure
Cyclosporine, dose and duration not stated here
limitations
This is the step that makes the magnesium loss a signalling failure rather than direct channel blockade, but the abstract reports the two falls together without demonstrating that one causes the other in this model.
organism
Rat model of cyclosporine nephrotoxicity
plain_language
Cyclosporine significantly decreased renal expression of epidermal growth factor in the same rat model.
primary_references
Expression of renal distal tubule transporters TRPM6 and NCC in a rat model of cyclosporine nephrotoxicity and effect of EGF treatment. (2011). https://pubmed.ncbi.nlm.nih.gov/21653632/ DOI: 10.1152/ajprenal.00116.2011
route
In vivo
tissue
Kidney
Cyclosporine: the complex that inhibits calcineurin, a second cyclophilin, and the transport step that decides exposure (2026-09-23) · lines 245–245
Original AI-assisted curation of seven primary studies resolved by PubMed title search, with every abstract read and all DOIs cross-checked against live PubMed metadata on 2026-09-23. No reference carries a recorded retraction, erratum or expression of concern. Each of the seven is a separate laboratory and each carries its own lineage key, so none of them can be counted twice as independent support. Study-specific concentrations, kinetic constants and limitations retained. Not publisher full text. · supports · Rat model of cyclosporine nephrotoxicity · source_derived_draft · unverified_draft
Cyclosporine significantly decreased renal expression of epidermal growth factor in the same rat model.
Complete structured claim and evidence
In control rats given epidermal growth factor, renal TRPM6 expression rose and the fractional excretion of magnesium fell.
Rat epidermal growth factor → Rat TRPM6 source_derived_draftungraded
Experimental context and source evidence
duration
Not stated here
evidence_access
Primary PubMed abstract and indexed metadata reviewed. Full-text method details not stated here remain unresolved.
experimental_model
Control rats
exposure
Epidermal growth factor administration
limitations
Measured in control animals, which establishes the route without establishing that it is the route cyclosporine breaks.
organism
Control rats
plain_language
In control rats given epidermal growth factor, renal TRPM6 expression rose and the fractional excretion of magnesium fell.
primary_references
Expression of renal distal tubule transporters TRPM6 and NCC in a rat model of cyclosporine nephrotoxicity and effect of EGF treatment. (2011). https://pubmed.ncbi.nlm.nih.gov/21653632/ DOI: 10.1152/ajprenal.00116.2011
route
In vivo
tissue
Distal convoluted tubule
Cyclosporine: the complex that inhibits calcineurin, a second cyclophilin, and the transport step that decides exposure (2026-09-23) · lines 256–256
Original AI-assisted curation of seven primary studies resolved by PubMed title search, with every abstract read and all DOIs cross-checked against live PubMed metadata on 2026-09-23. No reference carries a recorded retraction, erratum or expression of concern. Each of the seven is a separate laboratory and each carries its own lineage key, so none of them can be counted twice as independent support. Study-specific concentrations, kinetic constants and limitations retained. Not publisher full text. · supports · Control rats · source_derived_draft · unverified_draft
In control rats given epidermal growth factor, renal TRPM6 expression rose and the fractional excretion of magnesium fell.
Complete structured claim and evidence
Epidermal growth factor did not raise TRPM6 or lower the fractional excretion of magnesium in cyclosporine-treated rats, although it did both in controls.
Rat epidermal growth factor → Rat TRPM6 source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
duration
Not stated here
evidence_access
Primary PubMed abstract and indexed metadata reviewed. Full-text method details not stated here remain unresolved.
experimental_model
Cyclosporine-treated rats compared with controls
exposure
Epidermal growth factor administration during cyclosporine treatment
limitations
A measured null in the treated arm. It says the EGF route is not simply underfilled during cyclosporine exposure, and it does not say where the block sits.
organism
Cyclosporine-treated rats compared with controls
plain_language
Epidermal growth factor did not raise TRPM6 or lower the fractional excretion of magnesium in cyclosporine-treated rats, although it did both in controls.
primary_references
Expression of renal distal tubule transporters TRPM6 and NCC in a rat model of cyclosporine nephrotoxicity and effect of EGF treatment. (2011). https://pubmed.ncbi.nlm.nih.gov/21653632/ DOI: 10.1152/ajprenal.00116.2011
route
In vivo
tissue
Distal convoluted tubule
trigger_kind
machinery_impairment Imported condition classification; unverified.
Cyclosporine: the complex that inhibits calcineurin, a second cyclophilin, and the transport step that decides exposure (2026-09-23) · lines 267–267
Original AI-assisted curation of seven primary studies resolved by PubMed title search, with every abstract read and all DOIs cross-checked against live PubMed metadata on 2026-09-23. No reference carries a recorded retraction, erratum or expression of concern. Each of the seven is a separate laboratory and each carries its own lineage key, so none of them can be counted twice as independent support. Study-specific concentrations, kinetic constants and limitations retained. Not publisher full text. · supports · Cyclosporine-treated rats compared with controls · source_derived_draft · unverified_draft
Epidermal growth factor did not raise TRPM6 or lower the fractional excretion of magnesium in cyclosporine-treated rats, although it did both in controls.
Complete structured claim and evidence
Cyclosporine did not change renal expression of claudin-16 in the same rat model in which it lowered TRPM6, TRPM7, NCC and EGF.
Cyclosporine → Rat claudin-16 source_derived_draftungraded
Experimental context and source evidence
duration
Not stated here
evidence_access
Primary PubMed abstract and indexed metadata reviewed. Full-text method details not stated here remain unresolved.
experimental_model
Rat model of cyclosporine nephrotoxicity
exposure
Cyclosporine, dose and duration not stated here
limitations
A measured null that places the effect at the distal convoluted tubule rather than at the paracellular magnesium route of the thick ascending limb. Expression was the readout; paracellular permeability was not measured.
organism
Rat model of cyclosporine nephrotoxicity
plain_language
Cyclosporine did not change renal expression of claudin-16 in the same rat model in which it lowered TRPM6, TRPM7, NCC and EGF.
primary_references
Expression of renal distal tubule transporters TRPM6 and NCC in a rat model of cyclosporine nephrotoxicity and effect of EGF treatment. (2011). https://pubmed.ncbi.nlm.nih.gov/21653632/ DOI: 10.1152/ajprenal.00116.2011
route
In vivo
tissue
Kidney
Cyclosporine: the complex that inhibits calcineurin, a second cyclophilin, and the transport step that decides exposure (2026-09-23) · lines 278–278
Original AI-assisted curation of seven primary studies resolved by PubMed title search, with every abstract read and all DOIs cross-checked against live PubMed metadata on 2026-09-23. No reference carries a recorded retraction, erratum or expression of concern. Each of the seven is a separate laboratory and each carries its own lineage key, so none of them can be counted twice as independent support. Study-specific concentrations, kinetic constants and limitations retained. Not publisher full text. · supports · Rat model of cyclosporine nephrotoxicity · source_derived_draft · unverified_draft
Cyclosporine did not change renal expression of claudin-16 in the same rat model in which it lowered TRPM6, TRPM7, NCC and EGF.
Complete structured claim and evidence
Cyclosporine did not change renal expression of claudin-19 in the same rat model, reported alongside the unchanged claudin-16.
Cyclosporine → Rat claudin-19 source_derived_draftungraded
Experimental context and source evidence
duration
Not stated here
evidence_access
Primary PubMed abstract and indexed metadata reviewed. Full-text method details not stated here remain unresolved.
experimental_model
Rat model of cyclosporine nephrotoxicity
exposure
Cyclosporine, dose and duration not stated here
limitations
The two claudins were reported together as unchanged, so this null and the claudin-16 null are one measurement read twice and are not independent of each other.
organism
Rat model of cyclosporine nephrotoxicity
plain_language
Cyclosporine did not change renal expression of claudin-19 in the same rat model, reported alongside the unchanged claudin-16.
primary_references
Expression of renal distal tubule transporters TRPM6 and NCC in a rat model of cyclosporine nephrotoxicity and effect of EGF treatment. (2011). https://pubmed.ncbi.nlm.nih.gov/21653632/ DOI: 10.1152/ajprenal.00116.2011
route
In vivo
tissue
Kidney
Cyclosporine: the complex that inhibits calcineurin, a second cyclophilin, and the transport step that decides exposure (2026-09-23) · lines 289–289
Original AI-assisted curation of seven primary studies resolved by PubMed title search, with every abstract read and all DOIs cross-checked against live PubMed metadata on 2026-09-23. No reference carries a recorded retraction, erratum or expression of concern. Each of the seven is a separate laboratory and each carries its own lineage key, so none of them can be counted twice as independent support. Study-specific concentrations, kinetic constants and limitations retained. Not publisher full text. · supports · Rat model of cyclosporine nephrotoxicity · source_derived_draft · unverified_draft
Cyclosporine did not change renal expression of claudin-19 in the same rat model, reported alongside the unchanged claudin-16.
Complete structured claim and evidence
Renal magnesium loss is a well-known effect of cyclosporine treatment in people, and in this rat model the authors attribute it to downregulation of TRPM6 in the distal convoluted tubule.
Cyclosporine → Renal magnesium reabsorption source_derived_draftungraded
Experimental context and source evidence
duration
Not stated here
evidence_access
Primary PubMed abstract and indexed metadata reviewed. Full-text method details not stated here remain unresolved.
experimental_model
Rat model of cyclosporine nephrotoxicity, with the human observation as the stated background
exposure
Cyclosporine, dose and duration not stated here
limitations
The human magnesium loss is cited as established background in this report rather than measured in it. The rat measurement is the transporter expression and the fractional excretion, and the causal attribution between them is the authors' reading.
organism
Rat model of cyclosporine nephrotoxicity, with the human observation as the stated background
plain_language
Renal magnesium loss is a well-known effect of cyclosporine treatment in people, and in this rat model the authors attribute it to downregulation of TRPM6 in the distal convoluted tubule.
primary_references
Expression of renal distal tubule transporters TRPM6 and NCC in a rat model of cyclosporine nephrotoxicity and effect of EGF treatment. (2011). https://pubmed.ncbi.nlm.nih.gov/21653632/ DOI: 10.1152/ajprenal.00116.2011
route
In vivo
tissue
Renal magnesium handling
Cyclosporine: the complex that inhibits calcineurin, a second cyclophilin, and the transport step that decides exposure (2026-09-23) · lines 300–300
Original AI-assisted curation of seven primary studies resolved by PubMed title search, with every abstract read and all DOIs cross-checked against live PubMed metadata on 2026-09-23. No reference carries a recorded retraction, erratum or expression of concern. Each of the seven is a separate laboratory and each carries its own lineage key, so none of them can be counted twice as independent support. Study-specific concentrations, kinetic constants and limitations retained. Not publisher full text. · supports · Rat model of cyclosporine nephrotoxicity, with the human observation as the stated background · source_derived_draft · unverified_draft
Renal magnesium loss is a well-known effect of cyclosporine treatment in people, and in this rat model the authors attribute it to downregulation of TRPM6 in the distal convoluted tubule.
Complete structured claim and evidence
Cyclosporine significantly decreased renal expression of the thiazide-sensitive sodium-chloride cotransporter in the distal convoluted tubule, which the authors link to the renal sodium loss.
Cyclosporine → Rat thiazide-sensitive sodium-chloride cotransporter / Ncc source_derived_draftungraded
Experimental context and source evidence
duration
Not stated here
evidence_access
Primary PubMed abstract and indexed metadata reviewed. Full-text method details not stated here remain unresolved.
experimental_model
Rat model of cyclosporine nephrotoxicity
exposure
Cyclosporine, dose and duration not stated here
limitations
Rat expression data. Sodium loss is attributed rather than separately quantified in the abstract.
organism
Rat model of cyclosporine nephrotoxicity
plain_language
Cyclosporine significantly decreased renal expression of the thiazide-sensitive sodium-chloride cotransporter in the distal convoluted tubule, which the authors link to the renal sodium loss.
primary_references
Expression of renal distal tubule transporters TRPM6 and NCC in a rat model of cyclosporine nephrotoxicity and effect of EGF treatment. (2011). https://pubmed.ncbi.nlm.nih.gov/21653632/ DOI: 10.1152/ajprenal.00116.2011
route
In vivo
tissue
Distal convoluted tubule
Cyclosporine: the complex that inhibits calcineurin, a second cyclophilin, and the transport step that decides exposure (2026-09-23) · lines 311–311
Original AI-assisted curation of seven primary studies resolved by PubMed title search, with every abstract read and all DOIs cross-checked against live PubMed metadata on 2026-09-23. No reference carries a recorded retraction, erratum or expression of concern. Each of the seven is a separate laboratory and each carries its own lineage key, so none of them can be counted twice as independent support. Study-specific concentrations, kinetic constants and limitations retained. Not publisher full text. · supports · Rat model of cyclosporine nephrotoxicity · source_derived_draft · unverified_draft
Cyclosporine significantly decreased renal expression of the thiazide-sensitive sodium-chloride cotransporter in the distal convoluted tubule, which the authors link to the renal sodium loss.
Complete structured claim and evidence
Serum aldosterone was significantly lower in cyclosporine-treated rats, and the authors read the fall in the sodium-chloride cotransporter as following an inactivated renin-angiotensin-aldosterone system.
Cyclosporine → Rat serum aldosterone concentration source_derived_draftungraded
Experimental context and source evidence
duration
Not stated here
evidence_access
Primary PubMed abstract and indexed metadata reviewed. Full-text method details not stated here remain unresolved.
experimental_model
Rat model of cyclosporine nephrotoxicity
exposure
Cyclosporine, dose and duration not stated here
limitations
A hormone measurement in rats. The link from the lower aldosterone to the lower cotransporter is the authors' interpretation of two associated findings.
organism
Rat model of cyclosporine nephrotoxicity
plain_language
Serum aldosterone was significantly lower in cyclosporine-treated rats, and the authors read the fall in the sodium-chloride cotransporter as following an inactivated renin-angiotensin-aldosterone system.
primary_references
Expression of renal distal tubule transporters TRPM6 and NCC in a rat model of cyclosporine nephrotoxicity and effect of EGF treatment. (2011). https://pubmed.ncbi.nlm.nih.gov/21653632/ DOI: 10.1152/ajprenal.00116.2011
route
In vivo
tissue
Renin-angiotensin-aldosterone system
Cyclosporine: the complex that inhibits calcineurin, a second cyclophilin, and the transport step that decides exposure (2026-09-23) · lines 322–322
Original AI-assisted curation of seven primary studies resolved by PubMed title search, with every abstract read and all DOIs cross-checked against live PubMed metadata on 2026-09-23. No reference carries a recorded retraction, erratum or expression of concern. Each of the seven is a separate laboratory and each carries its own lineage key, so none of them can be counted twice as independent support. Study-specific concentrations, kinetic constants and limitations retained. Not publisher full text. · supports · Rat model of cyclosporine nephrotoxicity · source_derived_draft · unverified_draft
Serum aldosterone was significantly lower in cyclosporine-treated rats, and the authors read the fall in the sodium-chloride cotransporter as following an inactivated renin-angiotensin-aldosterone system.
Complete structured claim and evidence
Final cyclosporine concentrations were 29.3% higher in the berberine-treated group than in the group without berberine.
Berberine → Blood cyclosporine exposure source_derived_draftungraded
Experimental context and source evidence
evidence_span
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experimental_model
Randomized controlled transplant study with separate six-person pharmacokinetic arm
exposure
52 recipients per clinical arm; berberine 0.2 g three times daily for three months; six-person 12-day PK comparison
limitations
Observed interaction is clinically relevant, but the proposed CYP3A4 explanation was not uniquely established. Baseline change and between-group difference must not be confused.
nutrient_topic
Berberine research collection; topical membership is not evidence of a direct dietary effect. · Berberine
organism
Renal-transplant recipients
plain_language
A transplant medicine had higher blood concentrations with berberine.
primary_references
[berberine-p16133554] Effects of berberine on the blood concentration of cyclosporin A in renal transplanted recipients: clinical and pharmacokinetic study. (2005). https://pubmed.ncbi.nlm.nih.gov/16133554/ DOI: 10.1007/s00228-005-0952-3
tissue_or_cell_type
Cyclosporine blood concentrations
Berberine: metabolism, nutrient connections and drug interactions (2026-09-17) · lines 714–725
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Randomized controlled transplant study with separate six-person pharmacokinetic arm · source_derived_draft · unverified_draft
### berberine-cyclosporine-clinical Final cyclosporine concentrations were 29.3% higher in the berberine-treated group than in the group without berberine. Condition category: normal nutrient_topic: Berberine research collection; topical membership is not evidence of a direct dietary effect. plain_language: A transplant medicine had higher blood concentrations with berberine. organism: Renal-transplant recipients tissue_or_cell_type: Cyclosporine blood concentrations experimental_model: Randomized controlled transplant study with separate six-person pharmacokinetic arm limitations: Observed interaction is clinically relevant, but the proposed CYP3A4 explanation was not uniquely established. Baseline change and between-group difference must not be confused. exposure: 52 recipients per clinical arm; berberine 0.2 g three times daily for three months; six-person 12-day PK comparison evidence_span: {"source_cache": "artifacts/berberine-research/16133554.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "7a86b1b0f9ad77889da596b013f9f229556d53d825dac1b8bb2ba6ed094a68ad", "start_char": 0, "end_char": 2232, "text_sha256": "7a86b1b0f9ad77889da596b013f9f229556d53d825dac1b8bb2ba6ed094a68ad"} [berberine-p16133554] Effects of berberine on the blood concentration of cyclosporin A in renal transplanted recipients: clinical and pharmacokinetic study. (2005). https://pubmed.ncbi.nlm.nih.gov/16133554/ DOI: 10.1007/s00228-005-0952-3
Complete structured claim and evidence
The 3 mg/kg cyclosporine arm showed a 19.2% AUC increase with berberine.
Berberine → Blood cyclosporine exposure source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/berberine-research/16541194.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "1e1c8258a18a8214a1124f3624eff9cb67151c5f54393ff2e3e7322b3bdf53b5", "start_char": 0, "end_char": 1615, "text_sha256": "1e1c8258a18a8214a1124f3624eff9cb67151c5f54393ff2e3e7322b3bdf53b5"}
experimental_model
Two small healthy-volunteer pharmacokinetic experiments
exposure
3 mg/kg cyclosporine with a single 0.3 g berberine dose; separate 6 mg/kg cyclosporine after 10 days of berberine
limitations
Different cyclosporine doses and berberine schedules limit direct comparison. A null arm does not negate the positive arm or transplant finding.
nutrient_topic
Berberine research collection; topical membership is not evidence of a direct dietary effect. · Berberine
organism
Two groups of six healthy male volunteers
plain_language
Interaction size depended on the tested regimen.
primary_references
[berberine-p16541194] The effects of berberine on the pharmacokinetics of cyclosporin A in healthy volunteers. (2006). https://pubmed.ncbi.nlm.nih.gov/16541194/ DOI: 10.1358/mf.2006.28.1.962774
tissue_or_cell_type
Cyclosporine pharmacokinetics
Berberine: metabolism, nutrient connections and drug interactions (2026-09-17) · lines 740–751
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Two small healthy-volunteer pharmacokinetic experiments · source_derived_draft · unverified_draft
### berberine-cyclosporine-low-dose The 3 mg/kg cyclosporine arm showed a 19.2% AUC increase with berberine. Condition category: normal nutrient_topic: Berberine research collection; topical membership is not evidence of a direct dietary effect. plain_language: Interaction size depended on the tested regimen. organism: Two groups of six healthy male volunteers tissue_or_cell_type: Cyclosporine pharmacokinetics experimental_model: Two small healthy-volunteer pharmacokinetic experiments limitations: Different cyclosporine doses and berberine schedules limit direct comparison. A null arm does not negate the positive arm or transplant finding. exposure: 3 mg/kg cyclosporine with a single 0.3 g berberine dose; separate 6 mg/kg cyclosporine after 10 days of berberine evidence_span: {"source_cache": "artifacts/berberine-research/16541194.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "1e1c8258a18a8214a1124f3624eff9cb67151c5f54393ff2e3e7322b3bdf53b5", "start_char": 0, "end_char": 1615, "text_sha256": "1e1c8258a18a8214a1124f3624eff9cb67151c5f54393ff2e3e7322b3bdf53b5"} [berberine-p16541194] The effects of berberine on the pharmacokinetics of cyclosporin A in healthy volunteers. (2006). https://pubmed.ncbi.nlm.nih.gov/16541194/ DOI: 10.1358/mf.2006.28.1.962774
Complete structured claim and evidence
The separate 6 mg/kg cyclosporine arm found no significant pharmacokinetic change after repeated berberine.
Berberine → Blood cyclosporine exposure source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/berberine-research/16541194.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "1e1c8258a18a8214a1124f3624eff9cb67151c5f54393ff2e3e7322b3bdf53b5", "start_char": 0, "end_char": 1615, "text_sha256": "1e1c8258a18a8214a1124f3624eff9cb67151c5f54393ff2e3e7322b3bdf53b5"}
experimental_model
Two small healthy-volunteer pharmacokinetic experiments
exposure
3 mg/kg cyclosporine with a single 0.3 g berberine dose; separate 6 mg/kg cyclosporine after 10 days of berberine
limitations
Different cyclosporine doses and berberine schedules limit direct comparison. A null arm does not negate the positive arm or transplant finding.
nutrient_topic
Berberine research collection; topical membership is not evidence of a direct dietary effect. · Berberine
organism
Two groups of six healthy male volunteers
plain_language
Both outcomes remain visible with their distinct dosing conditions.
primary_references
[berberine-p16541194] The effects of berberine on the pharmacokinetics of cyclosporin A in healthy volunteers. (2006). https://pubmed.ncbi.nlm.nih.gov/16541194/ DOI: 10.1358/mf.2006.28.1.962774
tissue_or_cell_type
Cyclosporine pharmacokinetics
Berberine: metabolism, nutrient connections and drug interactions (2026-09-17) · lines 753–764
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Two small healthy-volunteer pharmacokinetic experiments · source_derived_draft · unverified_draft
### berberine-cyclosporine-null-arm The separate 6 mg/kg cyclosporine arm found no significant pharmacokinetic change after repeated berberine. Condition category: normal nutrient_topic: Berberine research collection; topical membership is not evidence of a direct dietary effect. plain_language: Both outcomes remain visible with their distinct dosing conditions. organism: Two groups of six healthy male volunteers tissue_or_cell_type: Cyclosporine pharmacokinetics experimental_model: Two small healthy-volunteer pharmacokinetic experiments limitations: Different cyclosporine doses and berberine schedules limit direct comparison. A null arm does not negate the positive arm or transplant finding. exposure: 3 mg/kg cyclosporine with a single 0.3 g berberine dose; separate 6 mg/kg cyclosporine after 10 days of berberine evidence_span: {"source_cache": "artifacts/berberine-research/16541194.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "1e1c8258a18a8214a1124f3624eff9cb67151c5f54393ff2e3e7322b3bdf53b5", "start_char": 0, "end_char": 1615, "text_sha256": "1e1c8258a18a8214a1124f3624eff9cb67151c5f54393ff2e3e7322b3bdf53b5"} [berberine-p16541194] The effects of berberine on the pharmacokinetics of cyclosporin A in healthy volunteers. (2006). https://pubmed.ncbi.nlm.nih.gov/16541194/ DOI: 10.1358/mf.2006.28.1.962774
Complete structured claim and evidence
In six transplant recipients, cyclosporine AUC rose 34.5% after 12 days of berberine.
Berberine → Cyclosporine A / ciclosporin A source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/berberine-research/16133554.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "7a86b1b0f9ad77889da596b013f9f229556d53d825dac1b8bb2ba6ed094a68ad", "start_char": 0, "end_char": 2232, "text_sha256": "7a86b1b0f9ad77889da596b013f9f229556d53d825dac1b8bb2ba6ed094a68ad"}
experimental_model
Randomized controlled transplant study with separate six-person pharmacokinetic arm
exposure
52 recipients per clinical arm; berberine 0.2 g three times daily for three months; six-person 12-day PK comparison
limitations
Observed interaction is clinically relevant, but the proposed CYP3A4 explanation was not uniquely established. Baseline change and between-group difference must not be confused.
nutrient_topic
Berberine research collection; topical membership is not evidence of a direct dietary effect. · Berberine
organism
Renal-transplant recipients
plain_language
A pharmacokinetic subset confirmed increased exposure; it is not an instruction to lower the prescribed dose.
primary_references
[berberine-p16133554] Effects of berberine on the blood concentration of cyclosporin A in renal transplanted recipients: clinical and pharmacokinetic study. (2005). https://pubmed.ncbi.nlm.nih.gov/16133554/ DOI: 10.1007/s00228-005-0952-3
tissue_or_cell_type
Cyclosporine blood concentrations
Berberine: metabolism, nutrient connections and drug interactions (2026-09-17) · lines 727–738
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Randomized controlled transplant study with separate six-person pharmacokinetic arm · source_derived_draft · unverified_draft
### berberine-cyclosporine-pk In six transplant recipients, cyclosporine AUC rose 34.5% after 12 days of berberine. Condition category: normal nutrient_topic: Berberine research collection; topical membership is not evidence of a direct dietary effect. plain_language: A pharmacokinetic subset confirmed increased exposure; it is not an instruction to lower the prescribed dose. organism: Renal-transplant recipients tissue_or_cell_type: Cyclosporine blood concentrations experimental_model: Randomized controlled transplant study with separate six-person pharmacokinetic arm limitations: Observed interaction is clinically relevant, but the proposed CYP3A4 explanation was not uniquely established. Baseline change and between-group difference must not be confused. exposure: 52 recipients per clinical arm; berberine 0.2 g three times daily for three months; six-person 12-day PK comparison evidence_span: {"source_cache": "artifacts/berberine-research/16133554.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "7a86b1b0f9ad77889da596b013f9f229556d53d825dac1b8bb2ba6ed094a68ad", "start_char": 0, "end_char": 2232, "text_sha256": "7a86b1b0f9ad77889da596b013f9f229556d53d825dac1b8bb2ba6ed094a68ad"} [berberine-p16133554] Effects of berberine on the blood concentration of cyclosporin A in renal transplanted recipients: clinical and pharmacokinetic study. (2005). https://pubmed.ncbi.nlm.nih.gov/16133554/ DOI: 10.1007/s00228-005-0952-3
Complete structured claim and evidence
Ppif-null hepatocytes and fibroblasts resist calcium-overload-induced death relative to wild type.
Mitochondrial cyclophilin D / PPIF → Calcium overload-induced cell death source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
compartment_description
Mitochondrial permeability-transition pathway
experimental_model
Ppif-null and cyclophilin-D-overexpressing mice; isolated mitochondria, hepatocytes and fibroblasts
limitations
Protection does not extend to all classical apoptotic stimuli; calcium nutrition was not manipulated.
nutrient_topic
Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium
organism
Mus musculus
plain_language
Removing cyclophilin D protects these cells against calcium-overload injury.
primary_references
[ca-baines2005] Loss of cyclophilin D reveals a critical role for mitochondrial permeability transition in cell death (2005). https://pubmed.ncbi.nlm.nih.gov/15800627/ DOI: 10.1038/nature03434
research_relationship_category
loss_of_function
tissue_or_cell_type
Primary hepatocytes and fibroblasts
trigger_kind
machinery_impairment Imported condition classification; unverified.
Calcium: mechanism-first literature curation (2026-09-17) · lines 849–860
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Ppif-null and cyclophilin-D-overexpressing mice; isolated mitochondria, hepatocytes and fibroblasts · source_derived_draft · unverified_draft
### ca-ppif-loss-calcium-death-resistance Ppif-null hepatocytes and fibroblasts resist calcium-overload-induced death relative to wild type. Condition category: machinery_impairment nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: Removing cyclophilin D protects these cells against calcium-overload injury. organism: Mus musculus tissue_or_cell_type: Primary hepatocytes and fibroblasts experimental_model: Ppif-null and cyclophilin-D-overexpressing mice; isolated mitochondria, hepatocytes and fibroblasts limitations: Protection does not extend to all classical apoptotic stimuli; calcium nutrition was not manipulated. research_relationship_category: loss_of_function compartment_description: Mitochondrial permeability-transition pathway [ca-baines2005] Loss of cyclophilin D reveals a critical role for mitochondrial permeability transition in cell death (2005). https://pubmed.ncbi.nlm.nih.gov/15800627/ DOI: 10.1038/nature03434
Complete structured claim and evidence
Calcineurin binds NFAT1 and supports its reversible dephosphorylated, nuclear-active state during calcium stimulation.
Calcineurin → NFAT1 / NFATC2 source_derived_draftungraded
Experimental context and source evidence
compartment_description
Cytosol and nucleus
experimental_model
Murine T-cell experiments, inhibitor/chelation interventions and protein-binding assays
limitations
NFAT1-specific evidence; do not assign this calcium response to all NFAT proteins or NFAT5.
nutrient_topic
Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium
organism
Mus musculus
plain_language
Calcineurin connects calcium signaling to NFAT1 activation.
primary_references
[ca-loh1996] Calcineurin binds the transcription factor NFAT1 and reversibly regulates its activity (1996). https://pubmed.ncbi.nlm.nih.gov/8631904/ DOI: 10.1074/jbc.271.18.10884
research_relationship_category
regulation
tissue_or_cell_type
T lymphocytes
Calcium: mechanism-first literature curation (2026-09-17) · lines 425–436
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Murine T-cell experiments, inhibitor/chelation interventions and protein-binding assays · source_derived_draft · unverified_draft
### ca-calcineurin-nfat1-regulation Calcineurin binds NFAT1 and supports its reversible dephosphorylated, nuclear-active state during calcium stimulation. Condition category: normal nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: Calcineurin connects calcium signaling to NFAT1 activation. organism: Mus musculus tissue_or_cell_type: T lymphocytes experimental_model: Murine T-cell experiments, inhibitor/chelation interventions and protein-binding assays limitations: NFAT1-specific evidence; do not assign this calcium response to all NFAT proteins or NFAT5. research_relationship_category: regulation compartment_description: Cytosol and nucleus [ca-loh1996] Calcineurin binds the transcription factor NFAT1 and reversibly regulates its activity (1996). https://pubmed.ncbi.nlm.nih.gov/8631904/ DOI: 10.1074/jbc.271.18.10884
Complete structured claim and evidence
Calcium/calmodulin binding folds the human calcineurin regulatory region and supports displacement of autoinhibition.
Calcium/calmodulin → Calcineurin source_derived_draftungraded
Experimental context and source evidence
compartment_description
Cytosol
experimental_model
Recombinant human alpha-calcineurin, regulatory fragments and calmodulin; spectroscopy and exchange mass spectrometry
limitations
Fragment and biochemical data support a regulatory mechanism; not tissue-level output.
nutrient_topic
Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium
organism
Homo sapiens
plain_language
Calcium-bound calmodulin helps switch on calcineurin.
primary_references
[ca-rumimasante2012] Structural basis for activation of calcineurin by calmodulin (2012). https://pubmed.ncbi.nlm.nih.gov/22100452/ DOI: 10.1016/j.jmb.2011.11.008
research_relationship_category
regulation
tissue_or_cell_type
Recombinant signaling proteins
Calcium: mechanism-first literature curation (2026-09-17) · lines 412–423
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Recombinant human alpha-calcineurin, regulatory fragments and calmodulin; spectroscopy and exchange mass spectrometry · source_derived_draft · unverified_draft
### ca-calmodulin-calcineurin-activation Calcium/calmodulin binding folds the human calcineurin regulatory region and supports displacement of autoinhibition. Condition category: normal nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: Calcium-bound calmodulin helps switch on calcineurin. organism: Homo sapiens tissue_or_cell_type: Recombinant signaling proteins experimental_model: Recombinant human alpha-calcineurin, regulatory fragments and calmodulin; spectroscopy and exchange mass spectrometry limitations: Fragment and biochemical data support a regulatory mechanism; not tissue-level output. research_relationship_category: regulation compartment_description: Cytosol [ca-rumimasante2012] Structural basis for activation of calcineurin by calmodulin (2012). https://pubmed.ncbi.nlm.nih.gov/22100452/ DOI: 10.1016/j.jmb.2011.11.008
Complete structured claim and evidence
Cyclosporin A or FK506 blocked ranelate-associated NFATc1 activation and blunted osteoblast replication and phenotypic gene expression.
Mouse calcineurin phosphatase complex → Mouse NFATc1 source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
evidence_access
Primary abstract
experimental_model
Murine osteoblast inhibitor experiments.
limitations
These inhibitors have broader biological effects; not a clinical interaction estimate.
nutrient_topic
Strontium collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Strontium
perturbation_agent
inhibits · Cyclosporine A / ciclosporin A Cyclosporin A or FK506 blocked ranelate-associated NFATc1 activation; the experiment used cyclosporin A as the calcineurin blocker. FK506 is the second agent and is not a ledger entity yet.
plain_language
Blocking the activating phosphatase interrupts the downstream response.
primary_references
Essential role of nuclear factor of activated T cells (NFAT)-mediated Wnt signaling in osteoblast differentiation induced by strontium ranelate. · 2010 · https://pubmed.ncbi.nlm.nih.gov/20554534/ · DOI 10.1074/jbc.M110.110502
trigger_kind
machinery_impairment Imported condition classification; unverified.
Strontium: calcium interactions, cellular mechanisms and mineralization (2026-09-19) · lines 126–132
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Murine osteoblast inhibitor experiments. · source_derived_draft · unverified_draft
## strontium-calcineurin-block Blocking the activating phosphatase interrupts the downstream response. Cyclosporin A or FK506 blocked ranelate-associated NFATc1 activation and blunted osteoblast replication and phenotypic gene expression. Model: Murine osteoblast inhibitor experiments. Limitations: These inhibitors have broader biological effects; not a clinical interaction estimate. Evidence access: Primary abstract Essential role of nuclear factor of activated T cells (NFAT)-mediated Wnt signaling in osteoblast differentiation induced by strontium ranelate. · 2010 · https://pubmed.ncbi.nlm.nih.gov/20554534/ · DOI 10.1074/jbc.M110.110502
Complete structured claim and evidence

Availability and dependencies

Each situation shows the normal role first, then what the sources report under a specific condition. A shortfall in the diet, a fault in the machinery, and a low blood reading are kept separate because they are not the same thing.

The EGF route to TRPM6 does not respond during cyclosporine exposure

Condition: machinery_impairment · Cyclosporine treatment, which in the same model lowered renal TRPM6, TRPM7 and EGF while leaving claudin-16 and claudin-19 unchanged.

Normal role: Epidermal growth factor raises TRPM6 in the distal convoluted tubule. In control rats given EGF, renal TRPM6 expression rose and the fractional excretion of magnesium fell.

Recorded consequence: Giving EGF to cyclosporine-treated rats raised neither TRPM6 nor magnesium retention, so supplying the signal does not reopen the route.

Scope: One rat model of cyclosporine nephrotoxicity, with expression and fractional excretion as the readouts.

The sources

Every document behind this chapter is preserved word for word. Open one to read it in full with its recorded conflicts marked in place.

Berberine: metabolism, nutrient connections and drug interactions (2026-09-17)AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · unverified_draftRead preserved source
Calcium: mechanism-first literature curation (2026-09-17)AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · unverified_draftRead preserved source
Cyclosporine: the complex that inhibits calcineurin, a second cyclophilin, and the transport step that decides exposure (2026-09-23)Original AI-assisted curation of seven primary studies resolved by PubMed title search, with every abstract read and all DOIs cross-checked against live PubMed metadata on 2026-09-23. No reference carries a recorded retraction, erratum or expression of concern. Each of the seven is a separate laboratory and each carries its own lineage key, so none of them can be counted twice as independent support. Study-specific concentrations, kinetic constants and limitations retained. Not publisher full text. · unverified_draftRead preserved source
Strontium: calcium interactions, cellular mechanisms and mineralization (2026-09-19)AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · unverified_draftRead preserved source

Recorded disagreements

Where two sources say different things, both are kept and the difference is explained. You can discuss a disagreement or propose a mechanism that might account for it.

Calcium-overload permeability transition is not a universal apoptosis pathwayBaines 2005 reports resistance to calcium-overload/oxidative injury after Ppif loss but retained susceptibility to several other death stimuli.Read the recorded disagreement

Open questions in this collection

Questions the curators could not answer from the sources in front of them, kept here with the reason each one is still open. These are gaps in this collection, not findings or proof that no one has studied them.

Does the cyclophilin A-cyclosporine complex reach calcineurin in the kidney at the concentrations that lower TRPM6?The magnesium mechanism is recorded as transporter and growth-factor expression with no calcineurin step measured in that tissue.
Is the mitochondrial isomerase that cyclosporine binds in the 1990 titration the same protein as the Ppif gene product?A 1990 activity and binding-site measurement sits on one side of that assignment and the ledger's existing Ppif-null record on the other. This collection does not merge them.
Does cyclosporine interact with P-glycoprotein in a way that matters beside the OATP1B1 step?ABCB1 is already in this ledger and berberine is already recorded as increasing its expression, but no primary source for a cyclosporine claim on it was read during this curation.
How much of the berberine-cyclosporine exposure rise is transport and how much is metabolism?The ledger records the exposure rise and separately records berberine inhibiting CYP3A4 phenotypic activity. Neither apportions the effect.
Does the fall in renal EGF cause the fall in TRPM6, or do both follow something upstream?EGF raised TRPM6 in control rats and failed to in treated rats, which is consistent with a broken EGF route and with a second lesion downstream of it.

Chapters are assembled from supplied drafts and curated literature summaries. Statements remain unverified against the primary studies, and the ledger is not medical advice.

Evidence, AI assistance and curation standards

Cyclosporine

The mechanisms

The immediate intracellular receptor of cyclosporin A is cyclophilin, a peptidyl-prolyl cis-trans isomerase, and drug binding inhibits that isomerase activity.

The effects of cyclosporin A are reported to follow from the formation of an inhibitory complex between the drug and its prolyl isomerase, and not from inhibition of the isomerase activity that drug binding also causes.

FK506 likewise acts by forming a drug-dependent complex with FKBP, and it is that complex, not the free drug, that binds and inhibits calcineurin.

The cyclophilin-cyclosporin A complex competitively binds and inhibits the calcium- and calmodulin-dependent phosphatase calcineurin.

Cyclophilin without cyclosporin A bound did not bind or inhibit calcineurin, and neither did FKBP alone, FKBP with rapamycin, or FKBP with the inactive analogue 506BD.

The FKBP-FK506 complex also competitively binds and inhibits calcineurin, making calcineurin the common target of two structurally unrelated immunophilin-drug complexes.

FK506 acts through a drug-dependent complex with FKBP, its own immediate immunophilin receptor, rather than through the free drug.

In the 2.8-angstrom crystal structure the cyclophilin A-cyclosporin A complex binds a composite surface formed by the catalytic and regulatory subunits of calcineurin, and unlike FKBP-FK506 it also interacts with Arg-122 at the calcineurin active site.

NFAT is assembled when an antigen-receptor signal drives a pre-existing cytoplasmic subunit into the nucleus to join a newly synthesised nuclear subunit, and cyclosporin A blocks translocation of the cytoplasmic component.

Transcription directed by NFAT is blocked in T cells treated with cyclosporin A, which is why the drug reaches the cytokine genes that coordinate the immune response.

Cyclosporin A inhibited OATP2-mediated uptake of labelled cerivastatin in transporter-expressing MDCKII cells with a Ki of 0.2 micromolar.

Cyclosporin A inhibited the in vitro metabolism of labelled cerivastatin only at concentrations above 30 micromolar, two orders of magnitude above the concentrations that inhibited its transport.

Heterologously expressed CYP3A4 produced three primary cyclosporine metabolites, AM1, AM9 and AM4N, with substrate inhibition observed for AM1 and AM9 formation.

CYP3A5 formed only AM9 from cyclosporine, not AM1 or AM4N, with substrate inhibition and an apparent Km of 11.3 micromolar.

CYP3A5 did not form AM1 from cyclosporine in the same comparison in which CYP3A4 did.

Microsomes from human kidney produced only AM9, and the rate of formation at 2 and 20 micromolar cyclosporine was positively associated with detectable CYP3A5 protein and with the CYP3A5*1 allele in 4 of the 20 kidneys tested.

Cyclosporine significantly decreased renal expression of the magnesium channel TRPM6 in a rat model of cyclosporine nephrotoxicity.

Cyclosporine significantly decreased renal expression of TRPM7 alongside TRPM6 in the same rat model.

Cyclosporine significantly decreased renal expression of epidermal growth factor in the same rat model.

In control rats given epidermal growth factor, renal TRPM6 expression rose and the fractional excretion of magnesium fell.

Epidermal growth factor did not raise TRPM6 or lower the fractional excretion of magnesium in cyclosporine-treated rats, although it did both in controls.

Cyclosporine did not change renal expression of claudin-16 in the same rat model in which it lowered TRPM6, TRPM7, NCC and EGF.

Cyclosporine did not change renal expression of claudin-19 in the same rat model, reported alongside the unchanged claudin-16.

Renal magnesium loss is a well-known effect of cyclosporine treatment in people, and in this rat model the authors attribute it to downregulation of TRPM6 in the distal convoluted tubule.

Cyclosporine significantly decreased renal expression of the thiazide-sensitive sodium-chloride cotransporter in the distal convoluted tubule, which the authors link to the renal sodium loss.

Serum aldosterone was significantly lower in cyclosporine-treated rats, and the authors read the fall in the sodium-chloride cotransporter as following an inactivated renin-angiotensin-aldosterone system.

Final cyclosporine concentrations were 29.3% higher in the berberine-treated group than in the group without berberine.

The 3 mg/kg cyclosporine arm showed a 19.2% AUC increase with berberine.

The separate 6 mg/kg cyclosporine arm found no significant pharmacokinetic change after repeated berberine.

In six transplant recipients, cyclosporine AUC rose 34.5% after 12 days of berberine.

Ppif-null hepatocytes and fibroblasts resist calcium-overload-induced death relative to wild type.

Calcineurin binds NFAT1 and supports its reversible dephosphorylated, nuclear-active state during calcium stimulation.

Calcium/calmodulin binding folds the human calcineurin regulatory region and supports displacement of autoinhibition.

Cyclosporin A or FK506 blocked ranelate-associated NFATc1 activation and blunted osteoblast replication and phenotypic gene expression.

Availability and dependencies

The sources

Recorded disagreements

Open questions in this collection