Investigation and evaluation of genetic polymorphisms of drug metabolizing

遗传多态性的发现使人们对人类的遗传变异有了更深刻的认识。人体内药物效应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。用于识别弱代谢者的可靠基因分型方案已经用于某些药物代谢酶，如CYP 2C 9，CYP 2C 19，CYP 2D 6和巯基嘌呤甲基转移酶，以预防某些药物的严重副作用和毒性。本研究主要分为以下三个部分：1.证实了尼古丁代谢的个体差异与CYP 2A 6基因多态性的关系。由于CYP 2A 6催化甲氧氟烷、氟烷、罗格酮等药物的代谢，因此CYP 2A 6基因多态性具有重要的临床意义。2、研究曲格列酮对人肝癌细胞的毒性作用及诱导细胞凋亡的作用。是苏吉 ...更多信息 提示曲格列酮的特异性肝毒性可能与肝细胞凋亡有关。此外，还研究了曲格列酮的一种新的醌环氧化物代谢产物的形成，该代谢产物对HepG 2细胞具有细胞毒性。由于环氧化物通常被认为是化学反应活性物质，本研究发现的一种新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、研究了人有机阴离子转运蛋白OATP-X（SLC 21 A6）和OATP-B（SLC 21 A9）的遗传多态性。进行日本人群等位基因频率和功能分析。在日本人群中，OATP-C^*1b和OATP-C^*5等位基因的频率分别为53.7%和0.7%。此外，还发现了一个新的等位基因OATP-C^*15，频率为10.3%。OATP-B^*3等位基因在日本人中的频率很高（30.9%），其内在功能性不到OATP-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，是引起个体间药效差异的因素之一。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