Investigation and evaluation of genetic polymorphisms of drug metabolizing

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Identification of genetic polymorphisms had led the profound understanding of the genetic variability in humans. Interindividual variation of drug effects in humans can be attributed in part to the difference in the genes that encoding drug metabolizing enzymes. The reliable genotyping protocols to identify poor metabolizers are already in practice for certain drug-metabolizing enzymes, such as CYP2C9, CYP2C19, CYP2D6, and thiopurine methyltransferase, for the prevention of severe side effects and toxicity from some medications. In this study, there are 3 parts as follows; 1. Relationship between interindividual difference in nicotine metabolism and CYP2A6 genetic polymorphism in humans was proved. Because CYP2A6 catalyzes the metabolism of some pharmaceuticals such as methoxyflurane, halothane, logigamone, the genetic polymorphism of CYP2A6 gene would be clinically important.; 2, Cytotoxicity and apoptosis produced by troglitazone in human hepatoma cells were investigated. It is sugge … More sted that a factor contributing to the idiosyncratic hepatptoxicity of troglitazone could be apoptosis in hepatocytes in human. In addition, the formation of a novel quinone epoxide metabolites of troglitazone with cytotoxic to HepG2 cells were studied. Since epoxides are generally regarded as the chemically reactive species, a novel metabolite found in this study may play a role in idiosyncrasy of troglitazone hepatotoxicity via individual differences either in the formation or degradation of this metabolite.; 3, The genetic polymorphism of human organic anion transporters OATP-X (SLC21A6) and OATP-B (SLC21A9) was studied. Allele frequencies in the Japanese population and functional analysis were performed. The frequencies of OATP-C^*1b and OATP-C^*5 alleles were determined as 53.7% and 0.7%, respectively in the Japanese population. Furthermore, a novel allele, OATP-C^*15, was also found with the frequency of 10.3%. The OATP-B^*3 allele was present at high frequency (30.9%) in Japanese and its intrinsic functionality was less than half that of OATP-B^*1. The newly found OATP-B allele as well as OATP-C alleles may influence physiological functions and be one of factors that cause inter-individual variations of drug effects. Less