Effect of Cyclosporine A on metabolism and HIF‐1[alpha] induction in APAP toxicity in mice

Abstract

Mitochondrial permeability transition (MPT) is a proposed mechanism for acetaminophen (APAP) toxicity. Cyclosporine A (CYC), an inhibitor of MPT, was previously shown to reduce ATP loss and cytochrome c in APAP toxicity, suggesting that prevention of MPT decreased oxidative stress (J Hep 2005; 42:110–116). In previous work, we found that HIF‐1α was induced in APAP toxicity and hypothesized that HIF‐1α was induced by oxidative stress. Thus, we tested the effect of CYC on HIF‐1α induction in APAP toxicity. CYC of 50 mg/kg (IP) was given after APAP (200 mg/kg IP) and mice were sacrificed at 1, 2 or 4 hr. Mean values for ALT were 2167 IU/L (±379) for APAP/veh mice and 963 IU/L (±317) for APAP/CYC mice at 4 hr (p<0.05). Hepatic glutathione (GSH) depletion was comparable in both groups. No APAP protein adducts were detected at 1 hr and were 40% at 2 and 4 hr in the APAP/CYC group compared to the APAP/veh group (p < 0.05). HIF‐1α expression was reduced in the APAP/CYC mice at 4 hr, compared to the APAP/veh mice. Subsequent studies of HIF‐1α expression were performed using dose ranging of CYC. CYC 20 mg/kg inhibited APAP metabolism. CYC 10 mg/kg was administered to mice after APAP and the mice were sacrificed at 30 or 60 min. ALT, GSH, and APAP protein adduct values were comparable in the two groups of mice at 30 and 60 min. HIF‐1α induction was comparable in the two APAP groups at 30 min. However, HIF‐1α induction was reduced by 40% (p<0.05) in the APAP/CYC mice at 60 min. Thus, in contrast to higher doses, CYC 10 mg/kg did not alter the metabolism of APAP but did reduce HIF‐1α induction. These data support the hypothesis that HIF‐1α induction in the early stages of APAP toxicity is secondary to oxidative stress and the inhibition of MPT. Grant support: DK075936