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JM Lunetta, K Sugiyama and MA Correia
Department of Pharmacology, University of California San Francisco 94143.
Administration of the allylbarbiturate secobarbital (SB) to phenobarbital-pretreated rats is known to result in structural and functional loss of hepatic cytochrome P-450 and generation of N- alkylated prosthetic heme derivatives. Isozyme-selective functional markers have led us to confirm P-450b as the isozyme selectively inactivated by the drug. In contrast to its inactivation by allylisopropylacetamide, such SB-inactivated P-450b is not amenable to structural and functional repair by exogenous heme, for reasons that remain unclear. In an effort to gain some insight, we have explored various possible mechanisms. In the course of these studies with rat liver microsomes enriched in P-450b as well as isolated purified P- 450b, we have found that, along with prosthetic heme alkylation, a significant fraction of the hemoprotein also undergoes drug-mediated alkylation of the apocytochrome, presumably at the active site. Accordingly, an equimolar ratio of irreversibly bound drug to functionally inactive residual P-450b chromophore is observed after incubation of the purified isozyme with SB and NADPH. Thus, P-450b- mediated oxidative metabolism of SB appears to partition not only between prosthetic heme alkylation and epoxidation but apoprotein alkylation as well.
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