Lai D Y, Myers S C, Woo Y T, Greene E J, Friedman M A, Argus M F, Arcos J C
Chem Biol Interact. 1979;28(1):107-26. doi: 10.1016/0009-2797(79)90118-2.
In vivo administration to rats of the mixed-function oxidase modifiers 3-methylcholanthrene (MC), pregnenolone-16 alpha-carbonitrile (PCN) or beta-naphthoflavnoe (beta-f) inhibits the hepatic microsome-catalyzed in vitro binding of dimethylnitrosamine (DMN) to DNA. This parallels their effect on DMN-demethylase I, regarded to be the sole activating step in DMN carcinogenesis and fails to account for the previously observed anomaly that MC and PCN inhibit, while beta-NF enhances, the hepatocarcinogenic activity of DMN. The in vitro binding of DMN is clearly dependent on microsomes and NADPH, and is strongly enhanced by soluble cytoplasmic proteins; the presence of the latter has no effect. however, on the relative response to pretreatment by the modifiers. In mice beta-NF enhances and PCN inhibits DMN-demethylase I; beta-NF has no effect on either the cytochrome P-450 level or on the LD50, while PCN strongly increases the cytochrome P-450 level but without influencing the LD50. Neither of the two modifiers has any effect in mice on the host-mediated mutagenicity of DMN in a dose-response study, except for the highest dose of DMN (200 mg/kg) where PCN pretreatment significantly enhanced mutagenicity. To account for the anomalous observations, other potential pathways of DMN metabolism have been explored. Whole rat liver nuclei or isolated nuclear membrane fractions contain no DMN-demethylase or diethylnitrosamine-deethylase activity. In a microsomal mixed-function amine-oxidase assay system neither purified enzyme preparations nor whole microsomes catalyze NADPH oxidation in the presence of DMN as substrate. In addition, the purified enzyme does not catalyze formaldehyde production in the DMN-demethylase assay system. Benzylamine, a typical inhibitor of mitochondrial monoamine oxidase (MAO), is a potent inhibitor of DMN-demethylase activity, but microsomes are devoid of MAO activity. Furthermore, purified MAO has no DMN-demethylase activity. The differential effect of modifiers on the carcinogenicity of DMN probably involves pathways other than DMN metabolism.
给大鼠体内注射混合功能氧化酶调节剂3-甲基胆蒽（MC）、孕烯醇酮-16α-腈（PCN）或β-萘黄酮（β-f）可抑制肝微粒体催化的二甲基亚硝胺（DMN）在体外与DNA的结合。这与它们对DMN-脱甲基酶I的作用相似，DMN-脱甲基酶I被认为是DMN致癌过程中的唯一激活步骤，但这无法解释之前观察到的异常现象，即MC和PCN会抑制DMN的致癌活性，而β-NF会增强其致癌活性。DMN的体外结合明显依赖于微粒体和NADPH，并且可被可溶性细胞质蛋白强烈增强；后者的存在对调节剂预处理的相对反应没有影响。在小鼠中，β-NF增强而PCN抑制DMN-脱甲基酶I；β-NF对细胞色素P-450水平或半数致死剂量（LD50）均无影响，而PCN可强烈增加细胞色素P-450水平，但不影响LD50。在一项剂量反应研究中，除了最高剂量的DMN（200 mg/kg）外，这两种调节剂对小鼠体内宿主介导的DMN致突变性均无影响，在该剂量下，PCN预处理可显著增强致突变性。为了解释这些异常观察结果，人们探索了DMN代谢的其他潜在途径。大鼠全肝细胞核或分离的核膜部分均不具有DMN-脱甲基酶或二乙基亚硝胺-脱乙基酶活性。在微粒体混合功能胺氧化酶测定系统中，无论是纯化的酶制剂还是全微粒体，在以DMN为底物时均不催化NADPH氧化。此外，纯化的酶在DMN-脱甲基酶测定系统中不催化甲醛生成。苄胺是线粒体单胺氧化酶（MAO）的典型抑制剂，是DMN-脱甲基酶活性的有效抑制剂，但微粒体缺乏MAO活性。此外，纯化的MAO没有DMN-脱甲基酶活性。调节剂对DMN致癌性的不同影响可能涉及DMN代谢以外的途径。
