FUNCTION OF CYTOCHROMES P450

细胞色素 P450 的功能

• 批准号: 6100824
• 负责人: F J GONZALEZ
• 金额: --
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 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/6100824
• 关键词: acetaminophen; benzene; caffeine; carcinogen testing; chemical carcinogen; chemical carcinogenesis; cytochrome P450; drug metabolism; enzyme activity; isozymes; laboratory mouse; liver neoplasms; mutagen testing; mutagens; pharmacokinetics; tissue /cell culture

In mammals, a large number of enzymes exist that metabolize drugs and other xenobiotics. Cytochrome P450s are among the most important of these enzymes that are involved in metabolism of most therapeutically- used drugs. In addition, P450s catalyze the metabolic-activation of chemical carcinogens. The P450s involved in xenobiotic metabolism are found in the CYP1, CYP2 and CYP3 families. Each of these families consist of two or more subfamilies. The fact that P450s can metabolically-activate toxins and procarcinogens in vitro implies that they are involved in toxicity's and cancer. However, it is not known whether P450s are required for the toxicity and carcinogenicity of chemicals in an intact animal. The only experiments suggestive of a role for P450s in cancer etiology are indirect chemically-induced transformation assays in cell culture, and genetic experiments in mice involving the Ah locus. No direct evidence is available to establish that P450s are necessary for carcinogenesis in an intact animal model system. To assess the potential contribution of P450s to acute chemical toxicity's and the process of chemical carcinogenesis, and to determine their roles, if any, in mammalian development and physiological homeostasis, P450-null mice were produced. P450s were selected for analysis based on their conservation of activities between mice and humans. CYP1A2, that is capable of metabolic activation of arylamine and heterocyclic amine carcinogens and CYP2E1, P450s that metabolizes a large number of low molecular weight toxins and cancer suspect chemicals were selected for analysis. CYP1A2 and CYP2E1-null mice were produced and found to be indistinguishable from wild-type mice having the P450s, indicating that they have no critical role in mammalian development or physiological homeostasis. Acute toxicity's studies revealed that CYP2E1-null mice mediate the hepatotoxic effects of the common analgesic acetaminophen and the genotoxicity found after benzene administration. These studies indicate that under condition conditions of acute chemical exposures, P450s are required for toxicity's. Studies are in progress to determine whether P450s are necessary for carcinogenesis in the neonatal mouse carcinogen bioassay.

在哺乳动物中，存在大量代谢药物的酶， 异生物质。细胞色素P450是最重要的 这些酶参与大多数治疗药物的代谢， 吸毒此外，P450还催化 化学致癌物参与异生物质代谢的P450是 发现于CYP 1、CYP 2和CYP 3家族。每一个家庭 由两个或多个亚科组成。事实上，P450可以 代谢活化毒素和原致癌物的体外研究表明， 它们与毒性和癌症有关。但殊不知 是否需要P450的毒性和致癌性 化学物质在一个完整的动物。唯一能暗示 癌症病因学中的P450是间接化学诱导的， 细胞培养中的转化试验和小鼠遗传实验 涉及到Ah位点。没有直接证据表明 P450在完整动物模型中是致癌所必需的 系统为了评估P450对急性化学物质 毒性和化学致癌过程，并确定 它们在哺乳动物发育和生理方面的作用，如果有的话， 为了保持体内平衡，产生P450缺失小鼠。选择P450用于 基于它们在小鼠和小鼠之间的活性保守性的分析， 人类CYP1A2，能够代谢活化芳胺， 杂环胺致癌物和CYP2E1，P450代谢a 大量的低分子量毒素和癌症可疑化学物质 被选中进行分析。产生CYP1A2和CYP2E1缺失小鼠 并且发现与具有P450的野生型小鼠没有区别， 表明它们在哺乳动物发育中没有关键作用，或 生理稳态急性毒性研究显示， CYP2E1基因敲除小鼠介导常用镇痛药的肝毒性作用 对乙酰氨基酚和苯后发现的遗传毒性。 这些研究表明，在急性化学条件下， 暴露，P450是毒性所必需的。研究正在进行中 以确定P450是否是在癌症中所必需的。 新生小鼠致癌物生物测定。