Role of Xenobiotic Metabolism in Cancer Susceptibility

在哺乳动物中，存在大量的酶来代谢药物和其他外源物质。细胞色素P450是这些酶中最重要的，参与了大多数治疗药物的新陈代谢。此外，P450还催化化学致癌物的代谢活化。参与异源代谢的P450存在于细胞色素P450、细胞色素P450、细胞色素P450和细胞色素P450家族中。这些家族中的每一个都由两个或更多的子家族组成。事实上，P450在体外可以代谢激活毒素和前致癌物，这意味着它们参与了毒性和癌症。然而，目前尚不清楚P450是否对完整动物体内的化学物质的毒性和致癌性是必需的。唯一表明P450在癌症病因学中的作用的实验是细胞培养中的间接化学诱导转化分析，以及涉及ah基因的小鼠遗传实验。在一个完整的动物模型系统中，没有直接证据表明P450是致癌所必需的。为了评估P450在急性化学毒性和化学致癌过程中的潜在作用，并确定它们在哺乳动物发育和生理动态平衡中的作用，我们制造了P450基因缺失的小鼠。最近的研究表明，CYP1B1缺失的小鼠没有表型，这表明这个保守的P450对于哺乳动物的发育或生理动态平衡不是必需的。用实验性多环芳烃7，12-二甲基苯并[a]蒽(DMBA)进行的致癌物生物测定表明，细胞色素P1B1是由该物质引起的淋巴癌和皮肤癌所必需的。这些研究证实了细胞色素P1B1在DMBA的3，4-环氧化物的形成中起着关键作用，DMBA最终的致癌代谢产物是DMBA-3，4-二醇，1，2-环氧化物。缺乏其他关键异源代谢酶的小鼠也被培育出来。微粒体环氧化物水解酶(Meh)缺失的小鼠被发现没有有害的表型，进一步证实了大多数异物代谢酶对发育和生理动态平衡不是关键的。与CYP1B1基因缺失的小鼠类似，meh基因缺失的动物对DMBA诱发的皮肤癌的敏感性大大降低，从而证实了meh在多环芳烃二醇环氧化物最终致癌代谢物的产生中所起的作用。

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 and the process of chemical carcinogenesis, and to determine their roles, if any, in mammalian development and physiological homeostasis, P450-null mice were produced. Recent studies have revealed that CYP1B1-null mice have no phenotype indicating that this well conserved P450 is not required for mammalian development or physiological homeostasis. A carcinogen bioassay using the experimental polycyclic aromatic hydrocarbon 7,12-dimethylbenz[a]anthracene (DMBA) revealed that CYP1B1 is required for lymphomagenesis and skin cancers caused by this agent. These studies establish a critical role of CYP1B1 in forming the 3,4-epoxide of DMBA that leads to the ultimate carcinogenic metabolite, DMBA-3,4-diol,1,2-epoxide. Mice lacking other critical xenobiotic-metabolizing enzymes have also been produced. Microsomal epoxide hydrolase (mEH) null mice were made and found to have no deleterious phenotype further establishing that most of the xenobiotic-metabolizing enzymes are not critical for development and physiological homeostasis. Similar to the CYP1B1-null mice, the mEH-null animals are considerably less susceptable to DMBA-induced skin cancer thus confirming the role of mEH in production of the diol-epoxide ultimate carcinogenic metabolite of polycyclic aromatic hydrocarbons.