Abstract

The roles of human P450 enzymes in the oxidation of xenobiotics have been shown to be determined by a) the ratio of Vmax to Km of individual P450 forms and b) the levels of expression of individual P450 forms In liver microsomes of human samples. We examined which P450 enzymes are most important in the 4-deethylation of 7-ethoxycoumarin and 6-hydroxylation of chlorzoxazone, two model reactions suggested to be catalyzed by several P450 enzymes, in liver microsomes of different human samples. Kinetic parameters for these two reactions were determined in 14 forms of recombinant human P450 expressed in baculovirus systems. Genetic polymorphisms In P450 genes are also important in understanding basis of different susceptibilities of individuals towards numerous xenobiotic chemicals. We examined the frequency distribution of CYP2A6 genetic polymorphisms in liver DNA of 39 Japanese and 43 Caucasians in the newly-developed two-step PCR method with modifications and the differences in CYP2A6-dependent catalytic activities were determined and compared in liver microsomes of individuals genotyped for CYP2A6 gene.

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