DRUG METABOLIZING ENZYMES IN HUMANS AND ANIMAL MODELS

成就：我们的实验室已经发现了影响人类代谢特定药物方式的CYP2C19、CYP2C9和最近的CYP2C8基因的多态。CYP2Cl9代谢药物奥美拉唑、莫苯妥因、安定、某些巴比妥酸盐、某些抗疟疾药物和杀虫剂甲拌磷。我们已经鉴定出11个等位基因。我们已经在一名苯妥英代谢的PM患者身上发现了一种新的缺陷的CYP2C9等位基因，他对该药物有过度的毒性。CYP2C9在肝素、甲苯丁胺、苯妥英、布洛芬和抗炎药等多种临床药物的代谢中起着非常重要的作用。我们从人类身上分离出了CYP2C8基因。在对该基因重新测序的3个种族的72名个体中发现了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了。CYP2C8*2主要在非裔美国人中发现，而CYP2C8*3主要在高加索人中发现。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似乎在人的心脏中有很好的表达，因此具有额外的临床意义。在体外，CYP2C8*2似乎对紫杉醇的代谢有一定的影响。我们还发现，CYP3C8*3在代谢重要的生理介质花生四烯酸方面存在缺陷。我们已经将CYP28定位于人的心脏，包括肌肉细胞和内皮细胞。因此，CYP2C8基因多态性可能在心脏病、冠状动脉疾病等疾病中具有重要意义。我们正在研究临床人群中暴露于紫杉醇的人群以及慢性心脏病患者的这些基因多态性的发生率。

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.