Acetaminophen hepatotoxicity and HIF-1α induction in acetaminophen toxicity in mice occurs without hypoxia. Toxicol Appl Pharmacol 2011 May 01;252(3):211-20
Date
02/15/2011Pubmed ID
21316383Pubmed Central ID
PMC3099476DOI
10.1016/j.taap.2011.02.005Scopus ID
2-s2.0-79954631441 (requires institutional sign-in at Scopus site) 23 CitationsAbstract
HIF-1α 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-1α. 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-1α 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-1α in APAP toxicity in the mouse. Time course studies using the hypoxia marker pimonidazole showed no staining for pimonidazole at 1 or 2h in B6C3F1 mice treated with APAP. Staining for pimonidazole was present in the midzonal to periportal regions at 4, 8, 24 and 48h 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; 10mg/kg) reduced HIF-1α induction in APAP treated mice at 1 and 4h and did not inhibit the metabolism of APAP (depletion of hepatic non-protein sulfhydryls and hepatic protein adduct levels). The data suggest that HIF-1α 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.
Author List
Chaudhuri S, McCullough SS, Hennings L, Letzig L, Simpson PM, Hinson JA, James LPAuthor
Pippa M. Simpson PhD Adjunct Professor in the Pediatrics department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AcetaminophenAlanine Transaminase
Animals
Chemical and Drug Induced Liver Injury
Cyclosporine
Dose-Response Relationship, Drug
Hypoxia
Hypoxia-Inducible Factor 1, alpha Subunit
Immunohistochemistry
Immunosuppressive Agents
Male
Mice
Mice, Inbred C57BL
Mitochondria, Liver
Nitroimidazoles
Oxidative Stress
Statistics, Nonparametric