FUNCTION OF CYTOCHROMES P450

在哺乳动物中，存在大量的酶来代谢药物和 其他外源生物。细胞色素P450是最重要的 这些参与新陈代谢的酶在治疗上- 吸毒。此外，P450还催化代谢激活 化学致癌物。参与异体代谢的P450是 发现于细胞色素P450 1、细胞色素P2和细胞色素P3家族。这些家庭都是 由两个或两个以上的子族组成。事实上，P450可以 体外新陈代谢激活的毒素和致癌物意味着 它们与毒性和癌症有关。然而，目前尚不清楚 是否需要P450才能发挥其毒性和致癌性 完整动物体内的化学物质。唯一能暗示一个角色的实验 因为癌症病因学中的P450是由间接化学诱导的 细胞培养中的转化分析和小鼠的遗传学实验 牵涉到了阿星座。没有直接证据可以证明 在完整的动物模型中，P450是致癌所必需的 系统。评估P450对急性化学物质的潜在贡献 毒性和化学致癌过程，并测定 它们在哺乳动物发育和生理方面的作用(如果有的话) 体内稳定，产生P450基因缺失的小鼠。P450被选为 基于它们在小鼠和小鼠之间活动保守性的分析 人类。细胞色素P1A2，能够代谢激活芳胺和 杂环胺类致癌物和代谢a的细胞色素P450和细胞色素P450 大量低分子毒素和致癌可疑化学物质 被选中进行分析。建立了细胞色素P4501A2和细胞色素P4502基因缺失小鼠 并被发现与携带P450的野生型小鼠难以区分， 表明它们在哺乳动物的发育或发育中没有关键作用 生理动态平衡。急性毒性研究显示， 常见镇痛剂对小鼠肝毒性的影响 对乙酰氨基酚和苯中毒后的遗传毒性。 这些研究表明，在急性化学物质条件下 暴露，毒性需要P450。研究正在进行中 为了确定P450是否在肿瘤的发生中是必需的 新生小鼠致癌物生物测定。

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.