Drug Metabolizing Enzymes In Humans And Animal Models

人类和动物模型中的药物代谢酶

• 批准号: 6504693
• 负责人: JOYCE GOLDSTEIN
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6504693
• 关键词: African American; antimalarial agents; antineoplastics; antiulcer drug; arachidonate; barbiturates; caucasian American; complementary DNA; cytochrome P450; drug metabolism; environmental contamination; enzyme activity; gene expression; gene mutation; genetic polymorphism; genetic screening; genetic susceptibility; human subject; nucleic acid sequence; paclitaxel; pesticides; phenytoin; racial /ethnic difference; site directed mutagenesis; toxin metabolism

ACCOMPLISHMENTS: We have identified genetic polymorphisms in the CYP family in humans which are responsible for the variable metabolism of certain drugs and environmental chemicals and altered susceptibility of humans to these chemicals. By resequencing efforts we have found 21SNPs in 72 individuals from 3 racial groups resequenced for human CYP2C8 including two alleles with coding changes : CYP2C8*2( Ile269Phe) and CYP2C8*3(Arg139Lys and Lys399Arg). Genetic tests showed CYP2C8*2 is found in African-Americans, and CYP2C8*3 primarily in Caucasians. Using recombinant cDNA expression systems, we found CYP2C8*3 is defective in the metabolism of the anticancer drug taxol as well as the endogenous compound arachidonic acid. CYP2C8 is expressed in human heart and blood vessels and is therefore of additional clinical interest. CYP2C9. A new null mutation was found in CY2C9 which decreased metabolism of the phenytoin by 85% in an African-American patient exhibiting severe clinical toxicity to the anticonvulsant phenytoin. The individual was homozygous for a new deletion mutant of CYP2C9. This is the first example of a null polymorphism in this clinically important enzyme. Population studies showed that the mutation was found in African-Americans but absent or rare in Caucasians. New polymorphisms have been discovered in CYP3A4 which metabolizes almost half of all clinically known drugs. Two amino acid changes affect catalytic activity toward the organophosphorus pesticide chlorpyrifos, and the hormone testosterone. The effects of these amino acid changes are being addressed in a bacterial cDNA expression system. Resequencing of CYP2C9 in 72 individuals has uncovered six new coding changes. The consequences of these are being studied using site-directed mutagenesis and cDNA expression systems. CYP2C19 metabolizes the antiulcer drug omeprazole, the anticonvulsant mephenytoin, valium, certain barbiturates, activates certain antimalarials, and sulfoxidizes the pesticide phorate. Nine new polymorphisms have been detected in CYP2C19. Their effects will be addressed in recombinant cDNA expression systems.

我们已经确定了人类CYP家族的遗传多态性，这些遗传多态性负责某些药物和环境化学物质的可变代谢，并改变了人类对这些化学物质的易感性。通过重测序，我们在3个种族的72个个体中发现了人类CYP2C8的21snp，包括两个编码改变的等位基因：CYP2C8*2（Ile269Phe）和CYP2C8*3（Arg139Lys和Lys399Arg）。基因测试显示CYP2C8*2在非裔美国人中发现，而CYP2C8*3主要在白种人中发现。利用重组cDNA表达系统，我们发现CYP2C8*3在抗癌药物紫杉醇和内源性化合物花生四烯酸的代谢中存在缺陷。CYP2C8在人类心脏和血管中表达，因此具有额外的临床意义。CYP2C9。在一名非裔美国患者中发现了一个新的CY2C9零突变，该突变使苯妥英的代谢降低了85%，对抗惊厥药苯妥英有严重的临床毒性。该个体是一个新的CYP2C9缺失突变体的纯合子。这是这种临床重要酶的第一个空多态性的例子。人口研究表明，这种突变在非裔美国人中发现，但在白种人中没有或罕见。新的多态性CYP3A4已被发现，代谢几乎一半的临床已知药物。两个氨基酸的变化影响对有机磷农药毒死蜱的催化活性和激素睾酮。这些氨基酸变化的影响正在细菌cDNA表达系统中得到解决。72个个体的CYP2C9重测序发现了6个新的编码变化。这些后果正在使用定点诱变和cDNA表达系统进行研究。CYP2C19代谢抗溃疡药物奥美拉唑、抗惊厥药物美苯妥英、安定、某些巴比妥类药物、激活某些抗疟药物和磺胺硫氧化农药磷。在CYP2C19中检测到9个新的多态性。它们的作用将在重组cDNA表达系统中得到解决。