Acetaminophen hepatotoxicity and HIF-1{alpha} induction in acetaminophen toxicity in mice occurs without hypoxia

Journal Article · Sun May 01 00:00:00 EDT 2011 · Toxicology and Applied Pharmacology

DOI:https://doi.org/10.1016/j.taap.2011.02.005· OSTI ID:21535285

Chaudhuri, Shubhra ^[1]; Hennings, Leah ^[2]; Letzig, Lynda ^[1]

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1. Department of Pediatrics, University of Arkansas for Medical Sciences (United States)
2. Department of Pathology, University of Arkansas for Medical Sciences (United States)

HIF-1{alpha} is a nuclear factor important in the transcription of genes controlling angiogenesis including vascular endothelial growth factor (VEGF). Both hypoxia and oxidative stress are known mechanisms for the induction of HIF-1{alpha}. Oxidative stress and mitochondrial permeability transition (MPT) are mechanistically important in acetaminophen (APAP) toxicity in the mouse. MPT may occur as a result of oxidative stress and leads to a large increase in oxidative stress. We previously reported the induction of HIF-1{alpha} in mice with APAP toxicity and have shown that VEGF is important in hepatocyte regeneration following APAP toxicity. The following study was performed to examine the relative contribution of hypoxia versus oxidative stress to the induction of HIF-1{alpha} in APAP toxicity in the mouse. Time course studies using the hypoxia marker pimonidazole showed no staining for pimonidazole at 1 or 2 h in B6C3F1 mice treated with APAP. Staining for pimonidazole was present in the midzonal to periportal regions at 4, 8, 24 and 48 h and no staining was observed in centrilobular hepatocytes, the sites of the toxicity. Subsequent studies with the MPT inhibitor cyclosporine A showed that cyclosporine A (CYC; 10 mg/kg) reduced HIF-1{alpha} induction in APAP treated mice at 1 and 4 h and did not inhibit the metabolism of APAP (depletion of hepatic non-protein sulfhydryls and hepatic protein adduct levels). The data suggest that HIF-1{alpha} induction in the early stages of APAP toxicity is secondary to oxidative stress via a mechanism involving MPT. In addition, APAP toxicity is not mediated by a hypoxia mechanism.

• OSTI ID: 21535285
• Journal Information: Toxicology and Applied Pharmacology, Vol. 252, Issue 3; Other Information: DOI: 10.1016/j.taap.2011.02.005; PII: S0041-008X(11)00051-2; Copyright (c) 2011 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; ISSN 0041-008X
• Country of Publication: United States
• Language: English

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60 APPLIED LIFE SCIENCES
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CYCLOSPORINE
GENES
GLUTATHIONE
GROWTH FACTORS
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LIVER CELLS
METABOLISM
MICE
OXIDATION
TOXICITY
AMINO ACIDS
ANIMAL CELLS
ANIMALS
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DIGESTIVE SYSTEM
DRUGS
GLANDS
IMMUNOSUPPRESSIVE DRUGS
MAMMALS
MITOGENS
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RESPONSE MODIFYING FACTORS
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