Component

Hepatic necrosis

Hepatic necrosis. Species, exposure and limitations are retained in each linked claim.

3 recorded relationships. Experimental role, claim status and evidence remain attached to each record.

Read recorded mechanisms Open recursive mind map

How nutrients influence it

Every nutrient with a recorded effect on this component, credited to the nutrient that acted rather than the chapter that recorded it. Open a nutrient to see the findings and the conditions they were measured under.

How nutrients reach it in more than one step

Chains of two or more recorded steps that end here, grouped by the nutrient they start from. Each step is a separate finding, so a chain is a route a mechanism could take, not proof that it does.

Tracing routes…

What it does

Every recorded relationship this component is part of, grouped by its role. Plain wording comes first; the technical statement follows.

Recorded relationships

What acts on it

  1. Leflunomide given 4 hours after a hepatotoxic dose of acetaminophen afforded significant protection from liver necrosis by serum alanine aminotransferase and histopathology at 8 and 24 hours, and the mechanism was not inhibition of cytochrome-P450-catalysed bioactivation or suppression of innate immunity but inhibition of acetaminophen-induced phosphorylation of c-Jun N-terminal protein kinase, preventing downstream Bcl-2 and Bcl-XL inactivation and protecting from mitochondrial permeabilization and cytochrome c release, while also preventing induction of inducible nitric oxide synthase and formation of peroxynitrite; protection was still obtained when given 8 hours after the dose.

    c-Jun N-terminal kinase → Hepatic necrosis source_derived_draftungraded
    Experimental context and source evidence
    availability_state
    biomarker_context Imported condition classification; unverified.
    evidence_span
    {"source_cache": "artifacts/paracetamol-research/17366662.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "7c7eb70728aa75fa3ac54f70703ce08d7a540b3a2a7da7e4797f27a6b1312dbb", "start_char": 0, "end_char": 1791, "text_sha256": "7c7eb70728aa75fa3ac54f70703ce08d7a540b3a2a7da7e4797f27a6b1312dbb"}
    experimental_model
    Male C57BL/6 mice given a hepatotoxic dose followed by leflunomide at 4 or 8 hours
    exposure
    750 milligrams per kilogram acetaminophen intraperitoneally, rescued with 30 milligrams per kilogram leflunomide
    limitations
    A rescue given hours after the dose, which separates the injury pathway from the bioactivation step. A mouse model at a dose far above therapeutic.
    nutrient_topic
    Paracetamol research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from the metabolites NAPQI and AM404. · Paracetamol
    organism
    Mouse
    plain_language
    The damage is done by a signalling kinase hours later, not by the chemistry of the metabolite alone, which is why a late rescue works.
    primary_references
    [apap-p17366662] Mitochondrial protection by the JNK inhibitor leflunomide rescues mice from acetaminophen-induced liver injury. (2007). https://pubmed.ncbi.nlm.nih.gov/17366662/ DOI: 10.1002/hep.21475
    tissue_or_cell_type
    Liver
    trigger_kind
    biomarker_context Imported condition classification; unverified.

    Paracetamol: the enzyme it reduces rather than blocks, the isoform that turned out not to exist, the metabolite that carries the analgesia, and the metabolite that destroys the liver (2026-09-22) · lines 415–426

    AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Male C57BL/6 mice given a hepatotoxic dose followed by leflunomide at 4 or 8 hours · source_derived_draft · unverified_draft

    ### apap-jnk-not-bioactivation Leflunomide given 4 hours after a hepatotoxic dose of acetaminophen afforded significant protection from liver necrosis by serum alanine aminotransferase and histopathology at 8 and 24 hours, and the mechanism was not inhibition of cytochrome-P450-catalysed bioactivation or suppression of innate immunity but inhibition of acetaminophen-induced phosphorylation of c-Jun N-terminal protein kinase, preventing downstream Bcl-2 and Bcl-XL inactivation and protecting from mitochondrial permeabilization and cytochrome c release, while also preventing induction of inducible nitric oxide synthase and formation of peroxynitrite; protection was still obtained when given 8 hours after the dose. Condition category: biomarker_context nutrient_topic: Paracetamol research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from the metabolites NAPQI and AM404. plain_language: The damage is done by a signalling kinase hours later, not by the chemistry of the metabolite alone, which is why a late rescue works. organism: Mouse tissue_or_cell_type: Liver experimental_model: Male C57BL/6 mice given a hepatotoxic dose followed by leflunomide at 4 or 8 hours limitations: A rescue given hours after the dose, which separates the injury pathway from the bioactivation step. A mouse model at a dose far above therapeutic. exposure: 750 milligrams per kilogram acetaminophen intraperitoneally, rescued with 30 milligrams per kilogram leflunomide evidence_span: {"source_cache": "artifacts/paracetamol-research/17366662.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "7c7eb70728aa75fa3ac54f70703ce08d7a540b3a2a7da7e4797f27a6b1312dbb", "start_char": 0, "end_char": 1791, "text_sha256": "7c7eb70728aa75fa3ac54f70703ce08d7a540b3a2a7da7e4797f27a6b1312dbb"} [apap-p17366662] Mitochondrial protection by the JNK inhibitor leflunomide rescues mice from acetaminophen-induced liver injury. (2007). https://pubmed.ncbi.nlm.nih.gov/17366662/ DOI: 10.1002/hep.21475
    Complete structured claim and evidence

Where it participates (unsigned role)

  1. Acetaminophen produced a biphasic response in the N-acyl ethanolamide and PPAR alpha system, with decreased PPAR alpha expression after 6 hours followed by a generalised increase of system components including PPAR alpha, NAPE-PLD and fatty acid amide hydrolase and of the N-acyl ethanolamides after 24 hours, confirmed in mice where gene expression of PPAR alpha and fatty acid amide hydrolase fell at 6 hours and rose by 24 hours, repeated administration decreased both and increased liver N-acyl ethanolamides with complete restoration after 15 days of rest, immunohistochemistry in a human case of acetaminophen hepatotoxicity confirmed the decrements, and damage-related alterations after repeated administration were aggravated in PPAR alpha-deficient mice.

    Paracetamol → The N-acyl ethanolamide and PPAR alpha anti-inflammatory system source_derived_draftungraded
    Experimental context and source evidence
    evidence_span
    {"source_cache": "artifacts/paracetamol-research/29056914.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "2ca7517052bab3c774f315af85f3aa8cdf810e43dc44444724bff46e2f1bdab3", "start_char": 0, "end_char": 2081, "text_sha256": "2ca7517052bab3c774f315af85f3aa8cdf810e43dc44444724bff46e2f1bdab3"}
    experimental_model
    Human HepG2 cells and mice given acute and repeated doses, with PPAR-alpha-deficient animals and a human case
    exposure
    0.5 to 20 millimolar in cells and 750 milligrams per kilogram in mice, acute and repeated over four days
    limitations
    Follows a lipid signalling system across cells, mice, knockouts and one human case. The biphasic time course is the informative part and complicates any single-timepoint reading.
    nutrient_topic
    Paracetamol research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from the metabolites NAPQI and AM404. · Paracetamol
    organism
    Human cells, mouse and human
    plain_language
    The same lipid system that makes the painkilling metabolite is knocked down by an overdose and then rebounds, and animals lacking it fare worse.
    primary_references
    [apap-p29056914] Acetaminophen-Induced Liver Injury Alters the Acyl Ethanolamine-Based Anti-Inflammatory Signaling System in Liver. (2017). https://pubmed.ncbi.nlm.nih.gov/29056914/ DOI: 10.3389/fphar.2017.00705
    tissue_or_cell_type
    Liver

    Paracetamol: the enzyme it reduces rather than blocks, the isoform that turned out not to exist, the metabolite that carries the analgesia, and the metabolite that destroys the liver (2026-09-22) · lines 441–452

    AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human HepG2 cells and mice given acute and repeated doses, with PPAR-alpha-deficient animals and a human case · source_derived_draft · unverified_draft

    ### apap-the-lipid-brake-fails-then-rebounds Acetaminophen produced a biphasic response in the N-acyl ethanolamide and PPAR alpha system, with decreased PPAR alpha expression after 6 hours followed by a generalised increase of system components including PPAR alpha, NAPE-PLD and fatty acid amide hydrolase and of the N-acyl ethanolamides after 24 hours, confirmed in mice where gene expression of PPAR alpha and fatty acid amide hydrolase fell at 6 hours and rose by 24 hours, repeated administration decreased both and increased liver N-acyl ethanolamides with complete restoration after 15 days of rest, immunohistochemistry in a human case of acetaminophen hepatotoxicity confirmed the decrements, and damage-related alterations after repeated administration were aggravated in PPAR alpha-deficient mice. Condition category: normal nutrient_topic: Paracetamol research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from the metabolites NAPQI and AM404. plain_language: The same lipid system that makes the painkilling metabolite is knocked down by an overdose and then rebounds, and animals lacking it fare worse. organism: Human cells, mouse and human tissue_or_cell_type: Liver experimental_model: Human HepG2 cells and mice given acute and repeated doses, with PPAR-alpha-deficient animals and a human case limitations: Follows a lipid signalling system across cells, mice, knockouts and one human case. The biphasic time course is the informative part and complicates any single-timepoint reading. exposure: 0.5 to 20 millimolar in cells and 750 milligrams per kilogram in mice, acute and repeated over four days evidence_span: {"source_cache": "artifacts/paracetamol-research/29056914.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "2ca7517052bab3c774f315af85f3aa8cdf810e43dc44444724bff46e2f1bdab3", "start_char": 0, "end_char": 2081, "text_sha256": "2ca7517052bab3c774f315af85f3aa8cdf810e43dc44444724bff46e2f1bdab3"} [apap-p29056914] Acetaminophen-Induced Liver Injury Alters the Acyl Ethanolamine-Based Anti-Inflammatory Signaling System in Liver. (2017). https://pubmed.ncbi.nlm.nih.gov/29056914/ DOI: 10.3389/fphar.2017.00705
    Complete structured claim and evidence

  2. Acetaminophen overdose is the leading cause of acute liver failure in Canada and around the world with approximately 4,500 hospitalisations each year in Canada and about 6% of those hospitalised developing liver injury including acute liver failure that may require transplant or lead to death, and on the Rumack-Matthew nomogram derived from patients not treated with antidote a serum concentration above 200 milligrams per litre at 4 hours carries a 60% incidence of severe hepatotoxicity and 5% mortality rising to 90% and 24% at 300 milligrams per litre, with treatment by N-acetylcysteine required above 140 milligrams per litre at 4 hours.

    Paracetamol → Acute liver failure source_derived_draftungraded
    Experimental context and source evidence
    availability_state
    biomarker_context Imported condition classification; unverified.
    evidence_span
    {"source_cache": "artifacts/paracetamol-research/36191122.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "859db1958aeb26b75a34a32e4dd1c4713dc7db413717cefe62a3659856db7568", "start_char": 0, "end_char": 3325, "text_sha256": "859db1958aeb26b75a34a32e4dd1c4713dc7db413717cefe62a3659856db7568"}
    experimental_model
    Review of point-of-care testing and antidote guidance for acute overdose
    exposure
    Serum acetaminophen concentration interpreted against the Rumack-Matthew nomogram
    limitations
    A health-technology review rather than primary research. The nomogram figures it quotes are derived from patients not treated with antidote, which is stated.
    nutrient_topic
    Paracetamol research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from the metabolites NAPQI and AM404. · Paracetamol
    organism
    Human
    plain_language
    Above a concentration that can be read off a chart, the liver fails in most people unless the antidote is given.
    primary_references
    [apap-p36191122] Point-of-Care Testing and N-Acetylcysteine for Acute Acetaminophen Overdose (2021). https://pubmed.ncbi.nlm.nih.gov/36191122/
    tissue_or_cell_type
    Liver
    trigger_kind
    biomarker_context Imported condition classification; unverified.

    Paracetamol: the enzyme it reduces rather than blocks, the isoform that turned out not to exist, the metabolite that carries the analgesia, and the metabolite that destroys the liver (2026-09-22) · lines 428–439

    AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Review of point-of-care testing and antidote guidance for acute overdose · source_derived_draft · unverified_draft

    ### apap-the-nomogram-and-the-antidote Acetaminophen overdose is the leading cause of acute liver failure in Canada and around the world with approximately 4,500 hospitalisations each year in Canada and about 6% of those hospitalised developing liver injury including acute liver failure that may require transplant or lead to death, and on the Rumack-Matthew nomogram derived from patients not treated with antidote a serum concentration above 200 milligrams per litre at 4 hours carries a 60% incidence of severe hepatotoxicity and 5% mortality rising to 90% and 24% at 300 milligrams per litre, with treatment by N-acetylcysteine required above 140 milligrams per litre at 4 hours. Condition category: biomarker_context nutrient_topic: Paracetamol research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from the metabolites NAPQI and AM404. plain_language: Above a concentration that can be read off a chart, the liver fails in most people unless the antidote is given. organism: Human tissue_or_cell_type: Liver experimental_model: Review of point-of-care testing and antidote guidance for acute overdose limitations: A health-technology review rather than primary research. The nomogram figures it quotes are derived from patients not treated with antidote, which is stated. exposure: Serum acetaminophen concentration interpreted against the Rumack-Matthew nomogram evidence_span: {"source_cache": "artifacts/paracetamol-research/36191122.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "859db1958aeb26b75a34a32e4dd1c4713dc7db413717cefe62a3659856db7568", "start_char": 0, "end_char": 3325, "text_sha256": "859db1958aeb26b75a34a32e4dd1c4713dc7db413717cefe62a3659856db7568"} [apap-p36191122] Point-of-Care Testing and N-Acetylcysteine for Acute Acetaminophen Overdose (2021). https://pubmed.ncbi.nlm.nih.gov/36191122/
    Complete structured claim and evidence

In the sources

Preserved passages that mention this component, quoted exactly. Open one to read it in context.

    This is a research prototype built from draft material. It is not medical advice, and its statements still await verification against the original studies.

    Evidence, AI assistance and curation standards