CHARACTERIZATION OF HUMAN P450S AND THEIR GENES

这个项目的主要目的是了解人类的作用 P450在化学致癌和药物治疗中的作用 人类P450 通过在各种系统中使用cDNA表达进行分析，包括 杆状病毒、牛痘病毒和类淋巴母细胞。 后者 通过合作研发协议实现商业化 （CRADA）与Gentest Corporation。 大量毒品和 致癌物质底物已被分析代谢的不同P450 forms. P450基因表达的多态性正在确定中。 一个 发现CYP 2C 9的等位基因变体，其具有Arg至Cys的变化 在残基144处。 这一变化导致华法林的显著差异 新陈代谢. A组中次要低活性变体的频率 华法林治疗的患者人群为0.192。 的新变种 发现CYP 2D 6具有改变的催化活性， 一组底物，包括异喹胍。 这种频率 变量非常低。 在该基因中发现了一种新的遗传多态性 编码CYP 2A 6，香豆素7-羟化酶。 两个变异等位基因， 编码无催化活性的蛋白质。 的频率 变异等位基因的范围从非洲裔美国人的0.025到美国人的0.48。 日本臣民。

The major objective of this project is to understand the role of human P450s in chemical carcinogenesis and drug therapy. Human P450s are analyzed through use of cDNA expression in a variety of systems including baculovirus, vaccinia virus and lymphoblastoid cells. The latter are commercialized through a cooperative research and development agreement (CRADA) with the Gentest Corporation. A large number of drug and carcinogen substrates have been analyzed for metabolism by different P450 forms. Polymorphisms in P450 gene expression are being determined. An allelic variant was discovered for CYP2C9 that has an Arg to Cys change at residue 144. This change results in a marked difference in warfarin metabolism. The frequency of the minor low activity variant in a population of patients on warfarin therapy is 0.192. A new variant of CYP2D6 was found that has altered catalytic activity toward a selective group of substrates, including debrisoquine. The frequency of this variant is very low. A new genetic polymorphism was found in the gene encoding CYP2A6, a coumarin 7-hydroxylase. Two variant alleles were found that encode catalytically inactive proteins. The frequencies of the variant alleles ranged from 0.025 in African Americans to 0.48 in Japanese subjects.