DRUG METABOLIZING ENZYMES IN HUMANS AND ANIMAL MODELS

成就：我们的实验室已经发现了CYP2C19，CYP2C9和最近的CYP2C8的多态性，这些多态性影响人类代谢特定药物的方式。CYP2C19代谢药物奥美拉唑、莫芬妥英、安定、某些巴比妥酸盐、某些抗疟药和农药甲拌磷。我们已经确定了11个等位基因。我们已经确定了一个新的缺陷CYP2C9等位基因被发现在个人谁是PM的代谢苯妥英和shoing过度毒性的药物。CYP2C9在肝素、甲苯磺丁脲、苯妥英、布洛芬、抗炎药等多种临床药物的代谢中起着重要作用。我们从人类中分离出了CYP2C8基因。在3个种族的72个个体中发现了20个SNPs。发现两个氨基酸变异的多态等位基因。 1）Ile269Phe（CYP2C8*2）和2）Arg139Lys和Lys399Arg（CYP2C8*3）。基因测试被设计出来。CYP2C8*2见于非裔美国人，而CYP2C8*3主要见于高加索人。 使用重组系统，CYP2C8*3在重组系统中代谢抗癌药物紫杉醇以及代谢内源性化合物方面存在缺陷。 CYP2C8似乎在人心脏中表达良好，因此具有额外的临床意义。CYP2C8*2似乎对体外紫杉醇代谢有适度影响。 我们还发现CYP3C8*3在代谢花生四烯酸（一种重要的生理介质）方面存在缺陷。 我们已经将CYP28定位于人心脏的肌肉和内皮细胞。因此，CYP2C8多态性可能在心脏病、冠状动脉疾病等方面具有潜在的重要性。我们正在研究暴露于紫杉醇的临床人群以及慢性心脏病患者中这些多态性的发生率。

ACCOMPLISHMENTS: Our laboratory has discovered polymorphisms in CYP2C19, CYP2C9, and more recently CYP2C8 which affect the way humans can metabolizes specific drugs. CYP2Cl9 metabolizes the drugs omeprazole, mophenytoin, valium, certain barbiturates, certain antimalarials, and the pesticide phorate. We have identified 11 alleles . We have identified a new defective CYP2C9 allele was found in an individual who was a PM for the metabolism of phenytoinand was shoing excessive toxicity to the drug. CYP2C9 is very important in metabolism of a wide variety of clincal drugs such as heparin, tolbutamide, phenytoin, ibuprofen, and antiinflammatories. We isolated the gene for CYP2C8 from humans. 20SNPs were found in 72 individuals from 3 racial groups resequenced for this gene. Two polymorphic alleles with amino acid variations were discovered. 1)Ile269Phe (CYP2C8*2) and 2) Arg139Lys and Lys399Arg (CYP2C8*3). Genetic tests were devised. CYP2C8*2 is found in African-Americans, and CYP2C8*3 primarily in Caucasians. Using recombinant systems, CYP2C8*3 is defective for metabolizing the anticancer drug taxol in a recombinant system as well as in metabolizing the endogenous compound . CYP2C8 appears to be well expressed in human heart and is therefore of additional clinical interest. CYP2C8*2 appears to have a modest effect on taxol metabolism in vitro. We have also found that CYP3C8*3 is defective in metabolizing arachidonic acid, an important physiological mediator. We have localize CYP28 to human heart, both muscle and endothelial cells. Therefor CYP2C8 polymorphisms could potentially have importance in heart disease, coronary artery disease, etc. We are examining clinical populations exposed to taxol as well as those with chronic heart disease for the incidence of these polymorphisms.