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

作者：Chaudhuri Shubhra; McCullough Sandra S; Hennings Leah; Letzig Lynda; Simpson Pippa M; Hinson Jack A; James Laura P^*

来源：Toxicology and Applied Pharmacology, 2011, 252(3): 211-220.

DOI：10.1016/j.taap.2011.02.005

• Hypoxia
• Acetaminophen
• Pimonidazole
• Mitochondria
• Glutathione
• Toxicity

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.

• 出版日期2011-5-1