| Budget Amount *help |
¥3,100,000 (Direct Cost: ¥3,100,000)
Fiscal Year 1998: ¥1,100,000 (Direct Cost: ¥1,100,000)
Fiscal Year 1997: ¥2,000,000 (Direct Cost: ¥2,000,000)
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| Research Abstract |
Phenobarbital pretreatment of male rats is known to increase the reductive metabolism of halothane and free radical formation under hypoxia that leads to lipid peroxidation, and ultimately results in extensive hepatotoxicity. It is also associated with a marked induction of microsomal heme oxygenase-1 (HO-1), suggesting that there is an alteration in heme metabolism in the liver. In this project, we examined heme metabolism in rats pretreated with phenobarbital, followed by exposure to halothane and hypoxia. Exposure of phenobarbital-pretreated rats to halothane-hypoxia caused a rapid increase in cytosolic free heme concentration, a decrease in the level of mRNA for the non- specific delta-aminolevulinate synthase, all of which were precede by a significant decrease in microsomal cytochrome P450 content in the liver There were also marked increases in two heat-shock proteins, namely, a transient but dramatic induction of HO-i mRNA reaching at the maximum on 6h, and a prolonged inductio
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n of heat shock protein 70 mRNA starting 2h. The level of HO-i protein was also increased and principally detected around the perivenular zone in the liver. Serum alanine transaminase (ALT) activity, an indicator of hepatic dysfunction, increase continuously with time, reaching the maximum at the end of the experimental period of 24h. Interestingly, hemin pretreatment of these animals not only induced hepatic HO-I, but also almost completely abrogated the halothane-induced hepatotoxicity in this model, as judged by a lack of induction of ALT activity, and normal histology of the liver. Our findings thus indicate that halothane-induced hepatotoxicity is not only due to its reductive metabolite formation, but also due to an increase in hepatic free heme concentration that is a potent prooxidant, and HO-i induction is an important protective response against such changes. This is also the first study to demonstrate that hemin pretreatment, thereby inducing HO-i prior to exposure to halothane, effectively prevents the halothane-induced hepatotoxicity. Less
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