DRUG METABOLIZING ENZYMES IN HUMANS AND ANIMAL MODELS

这些酶代谢药物和外源性物质， 这些酶中的一些解释了人类新陈代谢的可变性。我们 在CYP 2C 19中发现了三个新的缺陷， 抗惊厥药物美芬妥英和 抗溃疡药物奥美拉唑，并开发了其中两种基因测试 多态性 我们实验室开发的基因测试可以识别 约100%的东方人和约84%的高加索人PMS， 临床研究。 cDNA表达研究证实2C 19是一种新的表达载体。 奥美拉唑5-羟化酶原理。 CYP 2C 9多态性 对于抗糖尿病药物甲苯磺丁脲的PMS， CYP 2C 9-Leu等位基因在cDNA表达研究中亲和力降低 对于某些底物，例如抗凝剂华法林和 抗糖尿病药物甲苯磺丁脲。 cDNA表达和定点 诱变研究被用于鉴定 在CYP 2C亚家族的底物特异性中很重要。 氨基 氨基酸99和氨基酸220已被鉴定为对于 CYP 2C 19对奥美拉唑的选择性，但不足以赋予 对美芬妥英的选择性。 其他研究针对 确定CYP 2C 19中的其他缺陷，并开发和改进 基因检测的准确性。 定点诱变研究是 鉴定哪些另外的氨基酸赋予特异性， 另外的药物和内源性化学物质如奥美拉唑， 美芬妥英华法林和花生四烯酸 部分基因结构 可能是新的β 2C酶已被鉴定，基因克隆研究 正在试图确定这些基因的总基因结构， 在肝脏和肝外组织中鉴定其mRNA产物。 cDNA 表达研究旨在确定哪些CYP 2C酶 参与杀虫剂的代谢和抗疟疾药物的代谢 氯胍

The CYP enzymes metabolize drugs and xenobiotics, and polymorphisms in some of these enzymes account for variability in metabolism in man. We have identified three new defects in CYP2C19 responsible for poor metabolizers (PMS) of the anticonvulsant drug mephenytoin and the antiulcer drug omeprazole and developed genetic tests for two of these polymorphisms. Genetic tests developed in our laboratory identify approximately 100% of Oriental and approximately 84% of Caucasian PMS in clinical studies. cDNA expression studies confirm that 2C19 is the principle omeprazole 5-hydroxylase. A polymorphism in CYP2C9 responsible for PMS of the antidiabetic drug tolbutamide has been identified as the CYP2C9-Leu allele which has decreased affinity in cDNA expression studies for certain substrates such as the anticoagulant warfarin and the antidiabetic drug tolbutamide. cDNA expression and site-directed mutagenesis studies are being used to identify amino acids which are important in the substrate specificity of the CYP2C subfamily. Amino acid 99 and amino acid 220 have been identified as being important for selectivity of CYP2C19 for omeprazole but are not sufficient to confer selectivity for mephenytoin. Additional studies are directed toward identifying additional defects in CYP2C19 and developing and improving the accuracy of genetic testing. Site-directed mutagenesis studies are identifying which additional amino acids confer specificity for additional drugs and endogenous chemicals such as omeprazole, mephenytoin, warfarin and arachidonic acid. Partial gene structures for possibly new CYP 2C enzymes have been identified and gene cloning studies are attempting to identify the total gene structure for these genes, and identify their mRNA products in liver and extrahepatic tissues. cDNA expression studies are directed toward identifying which CYP2C enzymes are involved in pesticide metabolism, and metabolism of the antimalarial proguanil.