Prevention of halothane-induced hepatotoxicity by hemin pretreatment - Protective role of heme oxygenase-1 induction

Reductive metabolism of halothane in phenobarbital-pretreated rats is known to increase free radical formation that results in hepatotoxicity. It also is associated with a marked induction of microsomal heme oxygenase-1 (HO-1 ), suggesting that there is an alteration in heme metabolism. In this study , we examined heme metabolism in rats pretreated with phenobarbital, follow ed by exposure to halothane-hypoxia. In this model, there was a significant decrease in microsomal cytochrome P450 content in the liver, followed by a rapid increase in free heme concentration and a decrease in the level of m RNA for the nonspecific delta-aminolevulinate synthase. A transient but dra matic induction of HO-1 mRNA and a prolonged induction of heat shuck protei n 70 mRNA also occurred. The HO-1 protein was detected principally in the h epatocytes around the central vein. Serum alanine transaminase (ALT) activi ty, an indicator of hepatic dysfunction, increased continuously throughout the experiment. Hemin pretreatment induced hepatic HO-1 with abrogation of the halothane-induced hepatotoxicity in this model, as judged by ALT activi ty and normal histology. Our-findings in this study thus indicate that halo thane-induced hepatotoxicity is due not only to its reductive metabolite fo rmation, but also to an increase in hepatic free heme concentration which i s a potent prooxidant; HO-1 induction is an important protective response a gainst such changes. This is also the first study to demonstrate that hemin pretreatment, which induces HO-1 Frier To exposure to halothane, effective ly prevents halothane-induced hepatotoxicity. BIOCHEM PHARMACOL 59;7:871-88 0, 2000. (C) 2000 Elsevier Science Inc.