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: 6106559
• 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/6106559
• 关键词: arachidonate; complementary DNA; cytochrome P450; drug metabolism; enzyme activity; human tissue; laboratory mouse; pesticides

Aims: To identify genetic polymorphisms in the CYP2C subfamily in humans and laboratory animals which are responsilble for the variable metabolism by certain individuals to particular drugs. For these pathways, population studies show that humans can be divided into two groups , poor metabolizers (PMS) and extensive metabolizers (PMS). PMS have altered susceptibility to clinically administered drugs. These polymorphisms can potentially also affect metabolism of environmental compounds and affect susceptibility to environmental diseases. Human CYP2C19 is polymorphic. This enzyme metabolizes a variety of drugs including the antiulcer drug omeprazole and the anticonvulsant mephenytoin. We have identified nine mutant alleles (including five new alleles this year) contributing to the poor metabolizer phenotype and two wild-type alleles . Poor metabolizers make up 3-5% of Caucasian populations but 13-22% of Oriental populations. Two new poor metabolizer alleles were identified which were single amino acid mutations in exon 3. One was completely inactive and the other had approximately 10% of the wild type activitiy for tolbutamide and mephenytoin. Family studies showed another mutation in exon two segregated with CYP2C9*2 (a splice variant) and consisted of a new variant allele of this inactive protein. A fourth allele was in the heme binding region and was completely inactive. The last new mutation was a splice variant. These bring the accuracy of the genetic tests to ~96-98%. One poor metabolizer of a new drug glizipide and the antidiabetic drug tolbutamide was identified as a variant CYP2C9*3. The CYP28 gene structure has been established. A new CYP2C was identified in the dog which is polymorphic and present in only 10% of dogs. This may influence the toxicity and metabolism of certain compounds in the dog which is a test model for drug toxicology studies.

目的：确定遗传多态性， 人类和实验室动物中的CYP 2C亚家族， 负责某些个体的可变代谢， 特别的药物。对于这些途径，人口研究表明， 人类可分为两类，代谢不良者（PMS） 快速代谢型（PMS）经前综合症改变了 临床上使用的药物这些多态性可以 还可能影响环境化合物的代谢， 影响对环境疾病的易感性。人CYP 2C 19是 多态的这种酶代谢多种药物，包括 抗溃疡药奥美拉唑和抗惊厥药美芬妥英。 我们已经鉴定了9个突变等位基因（包括5个新等位基因 今年）有助于弱代谢表型和两个 野生型等位基因。低代谢者占白人的3-5% 人口，但13-22%的东方人口。两个新穷人 鉴定出单氨基酸的代谢型等位基因 外显子3的突变。一个完全不活动，另一个 对甲苯磺丁脲具有约10%的野生型活性， 美芬妥英家族研究显示第二外显子有另一个突变 与CYP 2C 9 *2（一种剪接变体）分离，并由一个 这种失活蛋白质的新变体等位基因。第四个等位基因位于 血红素结合区，完全无活性。最后一批新 突变是剪接变体。这些带来的准确性， 基因检测到~96- 98%。一种新药的弱代谢者 格列吡嗪和抗糖尿病药物甲苯磺丁脲被确定为 变体CYP 2C 9 *3。CYP 28基因结构已经被 确立了习在犬中发现了新的CYP 2C， 多态性和目前只有10%的狗。这可能影响 某些化合物在狗体内的毒性和代谢， 是药物毒理学研究的试验模型。