Molecular mechanism of inhaled anesthetic-induced hepatotoxicity

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We investigated the molecular mechanism of inhaled anesthetic-induced hepatotoxicity in vivo and in vitro. Exposure of phenobarbital-pretreated rats to halothane-hypoxia caused a rapid increase in cytosolic free heme concentration, which was preceded by a significant decrease in microsomal cytochrome P450 (CYP) content in the liver. There were also marked induction in heme oxygenase-1 (HO-1). hemin pretreatment of these animals not only induced hepatic HO-1 , but also almost completely abrogated the halothane-induced hepatotoxicity. These findings indicate that halothane-induced hepatotoxicity is due to an increase in hepatic free heme concentration that is a potent prooxidant, and HO-1 induction is an important protective response against such changes. Next, we examined the induction of HSP70 and HO-1, in rat livers pretreated with phenobarbital, followed by exposure to isoflurane, or halothane under hypoxic condition. The induction of HSP70 was observed by halothane-hypoxia treatment … More is higher than that by isoflurane-hypoxia treatment. Serum alanine aminotransferase (ALT) activity correlated well with the extent of centrilobular necrosis, showed similar changes with increases in HSP70. In contrast, HO-1 was induced only by halothane-hypoxia treatment, but not by other treatments. These findings demonstrate that there is a significant difference in hepatic injury, HO-1 and HSP70 induction, between halothane-hypoxia and isoflurane-hypoxia. Isoflurane is known to be safer than halothane, which may be in part accounted for by its lesser oxidative stress as assessed by a smaller induction of HSPs than halothane treatment. Finally, since inhaled anesthetics are metabolized by cytochrome P450-2E1 (CYP2E1) and inhaled anesthetics are derivates of carbon tetrachloride, the cytotoxic effects of CCl_4 in a liver cell line expressing CYP2E1 (HLE/2E1) in comparison to those in the mother cell line (HLE) were determined. The effects of CCl_4 on the gene expression of HSP70, a potential marker of oxidative stress, were also examined. The viability of HLE/2E1 cells after exposure to CCl_4 was significantly decreased compared with that of HLE cells. Northern blot analysis revealed that the HSP70 mRNA level was significantly increased after CCl_4 treatment in both cell lines, while the magnitude of its increase was much greater in HLE/2E1 cells than HLE cells. These results suggest that the oxidative stress induced by CYP2E1 plays an important role in the increase in cytotoxicity of CCl_4 in CYP2E1-overexpressing cells and that CYP2E1-overexpressing human liver cell line may be suitable for investigating the hepatotoxicity of volatile anesthetics. Less