Ye Y, Scharping C E, Holder G M
Department of Pharmacy, University of Sydney, NSW, Australia.
Carcinogenesis. 1995 Apr;16(4):787-93. doi: 10.1093/carcin/16.4.787.
The major and minor metabolites of the potent polycyclic aza-aromatic carcinogens 7,9-dimethylbenz[c]acridine and 7,10-dimethylbenz[c]acridine, and the stereochemistry of the dihydrodiol metabolites have been previously described. The metabolite distributions produced in incubations of the aza-aromatic compounds with liver microsomes from phenobarbital- and 3-methylcholanthrene-pretreated and untreated rats, and the mutagenicity in the Ames test are described in this paper. The major metabolites of each were the alcohols produced by oxidation of the methyl group on the 8,9,10,11-ring for control and phenobarbital-induced preparations, while with 3-methylcholanthrene-induced preparations both the 7- and 9- (or 10-) monoalcohols were formed. Total monofunctionalized dihydrodiol metabolites, the 5,6- and 3,4-isomers for 7,9-dimethylbenz[c]acridine, and the 3,4-, 5,6- and 8,9-isomers for 7,10-dimethylbenz[c]acridine, constituted approximately 10% of total metabolites. As well, the K-region arene oxide was formed in substantial amounts with both compounds, accompanied in the case of 7,10-dimethylbenz[c]acridine with some 8,9-oxide. When incubations were carried out in the presence of the epoxide hydrase inhibitor 3,3,3-trichloropropane-1,2-oxide, dihydrodiol formation was almost completely inhibited and relative amounts of both phenols and oxides increased. Secondary metabolites were also formed to approximately 10% of the total products. The mutagenicity of synthetic alcohols and isolated purified metabolites was determined in the Salmonella mammalian microsome plate assay (Ames test) with strain TA100. Limited amounts of metabolites isolated precluded extensive testing, but high mutagenicities were noted for all 3,4-dihydrodiol derivatives isolated. These exceeded those of the parent aza-aromatic hydrocarbons. Alcohols were also active but less so than the parent compounds. The activation of these two dimethylbenz[c]acridines to mutagens appears to be through bay-region diolepoxides following patterns seen in other aza-aromatic compounds and the polycyclic aromatic hydrocarbons.
强效多环氮杂芳烃致癌物7,9-二甲基苯并[c]吖啶和7,10-二甲基苯并[c]吖啶的主要和次要代谢产物，以及二氢二醇代谢产物的立体化学先前已有描述。本文描述了氮杂芳烃化合物与苯巴比妥和3-甲基胆蒽预处理及未处理大鼠的肝微粒体孵育产生的代谢产物分布，以及艾姆斯试验中的致突变性。对于对照和苯巴比妥诱导的制剂，每种化合物的主要代谢产物是8,9,10,11环上甲基氧化产生的醇类，而对于3-甲基胆蒽诱导的制剂，则形成了7-和9-（或10-）单醇。总单官能化二氢二醇代谢产物，7,9-二甲基苯并[c]吖啶的5,6-和3,4-异构体，以及7,10-二甲基苯并[c]吖啶的3,4-、5,6-和8,9-异构体，约占总代谢产物的10%。此外，两种化合物都大量形成了K区域的芳烃氧化物，在7,10-二甲基苯并[c]吖啶的情况下，还伴有一些8,9-氧化物。当在环氧化物水合酶抑制剂3,3,3-三氯丙烷-1,2-氧化物存在下进行孵育时，二氢二醇的形成几乎完全受到抑制，酚类和氧化物的相对含量增加。二级代谢产物也形成，约占总产物的10%。在沙门氏菌哺乳动物微粒体平板试验（艾姆斯试验）中，用TA100菌株测定了合成醇类和分离纯化代谢产物的致突变性。分离得到的代谢产物数量有限，无法进行广泛测试，但所有分离得到的3,4-二氢二醇衍生物都具有高致突变性。这些超过了母体氮杂芳烃的致突变性。醇类也有活性，但比母体化合物活性低。这两种二甲基苯并[c]吖啶激活为诱变剂的过程似乎是通过在其他氮杂芳烃化合物和多环芳烃中观察到的模式，即通过湾区二环氧物。
