Investigation and evaluation of genetic polymorphisms of drug metabolizing

遗传多态性的鉴定使人们对人类遗传变异性有了深刻的认识。人类体内药物作用的个体间差异可以部分归因于编码药物代谢酶的基因的差异。对于某些药物代谢酶，如CYP2C9、CYP2C19、CYP2D6和硫嘌呤甲基转移酶，为了防止某些药物的严重副作用和毒性，已经有了可靠的基因分型方案来识别不良代谢物。本研究主要分为以下三个部分：1. 证实了人类尼古丁代谢的个体间差异与CYP2A6基因多态性之间的关系。由于CYP2A6对甲氧基氟醚、氟烷、洛格甘酮等药物的代谢具有催化作用，因此CYP2A6基因的遗传多态性在临床上具有重要意义。2、研究了曲格列酮对人肝癌细胞的细胞毒性和凋亡作用。结果表明，曲格列酮的特异性肝毒性可能与肝细胞凋亡有关。此外，我们还研究了曲格列酮对HepG2细胞具有细胞毒性的新型环氧醌代谢物的形成。由于环氧化物通常被认为是化学活性物质，本研究中发现的一种新的代谢物可能通过该代谢物形成或降解的个体差异在曲格列酮肝毒性的特异性中发挥作用。3、研究了人体有机阴离子转运蛋白OATP-X （SLC21A6）和OATP-B （SLC21A9）的遗传多态性。对日本人群的等位基因频率和功能进行了分析。otp - c ^*1b和otp - c ^*5等位基因在日本人群中的频率分别为53.7%和0.7%。此外，还发现了一个新的等位基因otp - c ^*15，频率为10.3%。otp - b ^*3等位基因在日本人中存在频率较高（30.9%），其内在功能不到otp - b ^*1的一半。新发现的OATP-B等位基因和OATP-C等位基因可能影响生理功能，是引起药物作用个体间差异的因素之一。少

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