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: 5202095
• 负责人: J A 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/5202095
• 关键词: African American; Asian Americans; alleles; antimalarial agents; antineoplastics; antiulcer drug; caucasian American; complementary DNA; cyclophosphamide; cytochrome P450; drug metabolism; human subject; isozymes; molecular cloning; polymerase chain reaction; racial /ethnic difference; site directed mutagenesis; tolbutamide; yeasts

Certain CYP enzymes are polymorphic in man. One polymorphism affects the metabolism of mephenytoin and the commonly used antiulcer drug omeprazole as well as antimalarials and certain other drugs. This polymorphism varies in different racial populations. We have cloned and identified the two principle defects. We have developed diagnostic PCR tests for the two defects. The specificity of the tests are 100% and the sensitivity is ~93% in Caucasians and 100% in Orientals. These account for 100% of Oriental poor metabolizers and >90% of Caucasian and >90% of black poor metabolizers. We have examined the frequency of these defects in large numbers of Caucasians, Japanese, Chinese, Filipinos, and American black populations. The first defect m1 accounts for 75-90% of poor metabolizers, while the 2nd defect m2 accounts for the remainder of Oriental PMs but is rare in Caucasians. The allele frequencies varies in different racial groups. This polymorphism accounts for decreased ability to metabolize the drug omeprazole in vivo. We have also identified two normal wild-type alleles. We have expressed the cDNAs for all known members of the 2C subfamily in yeast and shown that CYP2C19 and CYP3A are the principal omeprazole 5'-hydroxylases while other CYP2C enzymes have little activity. We are testing which amino acids are important in this function by site-directed mutagenesis. DNA from two individuals who metabolize tolbutamide poorly has been sequenced and two potential defects have been identified. The allele frequency of these alleles have been determined in Caucasians, blacks, and Orientals. These alleles is being tested toward the drug tolbutamide and the anticancer agent cyclophosphamide.

某些 CYP 酶在人体中具有多态性。 一种多态性影响 美芬妥英与常用抗溃疡药奥美拉唑的代谢 以及抗疟药和某些其他药物。这种多态性 不同种族人群的情况有所不同。我们克隆并鉴定了 两个主要缺陷。我们为这两种疾病开发了诊断性 PCR 检测 缺陷。测试的特异性为 100%，敏感性为 白种人约为 93%，东方人约为 100%。这些占了100% 东方人代谢能力较差，>90% 的白种人和 >90% 的黑人贫穷 代谢者。 我们已经检查了大范围内这些缺陷的频率 白种人、日本人、中国人、菲律宾人和美国黑人的数量 人口。 第一缺陷m1占不良的75-90% 代谢者，而第二个缺陷 m2 则占剩余部分 东方人PM但在白人中很少见。等位基因频率变化 不同的种族群体。这种多态性导致能力下降 在体内代谢药物奥美拉唑。 我们还确定了两个 正常野生型等位基因。 我们已经表达了所有已知的 cDNA 酵母 2C 亚家族的成员，并表明 CYP2C19 和 CYP3A 是 主要的奥美拉唑 5'-羟化酶，而其他 CYP2C 酶则具有 活动很少。 我们正在测试哪些氨基酸在此方面很重要 通过定点突变发挥作用。来自两个人的 DNA 代谢不良的甲苯磺丁脲已被测序，并且有两种潜在的 已发现缺陷。这些等位基因的等位基因频率 已在白种人、黑人和东方人中确定。 这些等位基因是 正在对药物甲苯磺丁脲和抗癌剂进行测试 环磷酰胺。