FUNCTION OF CYTOCHROMES P450

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 已知这些酶参与大多数人的代谢， 治疗用药剂。P450也是关键， 前诱变剂和前致癌剂的代谢活化。P450已知 在CYP 1、CYP 2和CYP 3家族中发现了代谢外源性物质。 这些家族中的每一个家族由两个或更多个亚家族组成， P450的形成。有一个问题， 解决的是P450是否需要化学致癌作用， 一只完整的动物事实上，P450可以代谢激活 前致癌物意味着它们参与了 化学致癌作用然而，唯一的实验表明， P450在癌症病因学中的作用是间接化学诱导的 细胞培养中的转化试验和小鼠遗传实验 涉及到Ah位点。然而，没有直接证据表明， 证实了P450是完整细胞癌变所必需的 动物模型系统为了评估生理作用，如果有的话， P450及其对化学过程的潜在贡献 在致癌作用中，产生P450缺失小鼠。CYP 1A 2和CYP 2 E1-null 小鼠与具有P450的小鼠无法区分，表明 它们在哺乳动物的发育或生理上没有关键作用， 体内平衡使用咖啡因的药代动力学研究显示大鼠CYP 1A 2 负责该药物代谢且代谢是有速率的 限制其尿排泄。发现CYP 2 E1缺失小鼠 对乙酰氨基酚和苯的毒性有抵抗力， 表明CYP 2 E1是参与的主要P450 这些化学物质的代谢活化。致癌生物测定 目前正在进行中，以确定P450在 各种化学物质包括4-氨基联苯， 食物诱变剂和非那西丁。

In mammals, a large number of enzymes exist that metabolize drugs and other xenobiotics. Cytochrome P450s are among the most important of these enzymes and they are known to be involved in metabolism of most therapeutically-used agents. The P450s are also critical in the metabolic-activation of promutagens and procarcinogens. P450s known to metabolize xenobiotics are found in the CYP1, CYP2 and CYP3 families. Each of these families consist of two or more subfamilies containing the individual P450 forms. One question that has not been directly addressed is whether P450s are required for chemical carcinogenesis in an intact animal. The fact that P450s can metabolically-activate procarcinogens implies that they are involved in the process of chemical carcinogenesis. However, 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. However, no direct evidence is available to establish that P450s are necessary for carcinogenesis in an intact animal model system. To assess the physiological role, if any, for P450s and their potential contribution to the process of chemical carcinogenesis, P450-null mice were produced. CYP1A2 and CYP2E1-null mice were indistinguishable from mice having the P450s, indicating that they have no critical role in mammalian development or physiological homeostasis. Pharmacokinetic studies using caffeine showed rat CYP1A2 is responsible for metabolism of this drug and that metabolism is rate limiting for its urinary excretion. The CYP2E1-null mice were found to be resistant to the toxicity of acetaminophen and benzene as compared to normal mice indicating that CYP2E1 is the principal P450 involved in-metabolic activation of these chemicals. Carcinogenesis bioassays are currently in progress to determine the role of P450s in the hepatocarcinogenesis of various chemicals including 4-aminobiphenyl, food mutagens and phenacetin.