Felton J S, Nebert D W
J Biol Chem. 1975 Sep 10;250(17):6769-78.
A bacterial mutagenesis assay and genetic differences in microsomal CO-binding cytochromes were combined in vitro to evaluate the metabolic activation of several known carcinogens to frameshift mutagens. With the use of liver fractions from C57BL/6N and DBA/2N control mice and mice treated in vivo with 3-methylcholanthrene, beta-naphthoglavone, phenobarbital, or 2,3,7,,-tetrachlorodibenzo-p-dioxin, the in vitro mutagenicity of 3-methylcholanthrene, 6-aminochrysene, and 2-acetylaminofluorene --but not benzo[a]pyrene==is closely associated with the genetically mediated difference in both aromatic hydrocarbon-inducible aryl hydrocarbon (benzo[a]pyrene) hydroxylase activity and new cytochrome P1-450 formation; such an association between 7,12-dimethylbenz[a]anthracene or benz[a]anthracene activation to mutagens in vitro and these genetic differences between C57BL/6N and DBA/2N mouse strains in uncertain. The Salmonella typhimurium histidine mutant TA1538 is more effective than tester strains TA1537 and TA1535 in the determination of 3-methylcholanthrene mutagenesis in vitro. The relationships between the histidine revertant rate as a function of both liver protein concentration per plate and mutagen concentration per plate are illustrated for 3-methylcholanthrene, benzo[a]pyrene, 6-aminochrysene, and 2-acetylaminofluorene. With the use of offspring from the appropriate genetic crosses, the aromatic hydrocarbon-inducible hydroxylase activity appears to be expressed as an autosomal dominant trait, whereas the mutagenesis of 3-methylcholanthrene in vitro appears to be expressed additively; this apparent discrepancy probably reflects different proportional amounts of phenolic benzo[a]pyrene, compared with mutagenic 3-methylcholanthrene metabolites, formed by the monooxygenase(s). 3-Methylcholanthrene, 6-aminochrysene, and 2-acetylaminofluorene--but not benzo[a]pyrene--are each more mutagenic in vitro per molecule of cytochrome P1-450 than per molecule of CO-binding cytochrome other than P1450. Diethylmaleate, a compound which depletes flutathione content in liver, and 1,1,1-trichloropropene-2,3-epoxide, an inhibitor of epoxide hydrase (EC 4.2.1.63), were also studied in vitro. Diethylmaleate, and especially 1,1,1-trichloropropene-2,3-epoxide, increases the mutagenicity of benzo[a]pyrene, whereas no increases occur with 3-methylcholanthrene, 6-aminochrysene, or 2-acetylaminofluorene activation to mutagens in vitro. Both diethylmaleate and 1,1,1-trichloropropene-2,3-epoxide cause decreases in 2-acetylaminofluorene mutagenesis in vitro when liver fractions from phenobarbital-treated mice are used.
将细菌诱变试验与微粒体一氧化碳结合细胞色素的遗传差异相结合,在体外评估几种已知致癌物向移码诱变剂的代谢活化作用。使用来自C57BL/6N和DBA/2N对照小鼠以及经体内3-甲基胆蒽、β-萘黄酮、苯巴比妥或2,3,7,8-四氯二苯并-p-二噁英处理的小鼠的肝匀浆,3-甲基胆蒽、6-氨基 Chrysene和2-乙酰氨基芴(而非苯并[a]芘)的体外诱变性与芳烃诱导的芳烃(苯并[a]芘)羟化酶活性和新的细胞色素P1-450形成中的遗传介导差异密切相关;7,12-二甲基苯并[a]蒽或苯并[a]蒽在体外活化成诱变剂与C57BL/6N和DBA/2N小鼠品系之间的这些遗传差异之间的这种关联尚不确定。鼠伤寒沙门氏菌组氨酸突变体TA1538在体外测定3-甲基胆蒽诱变性方面比测试菌株TA1537和TA1535更有效。给出了3-甲基胆蒽、苯并[a]芘、6-氨基 Chrysene和2-乙酰氨基芴的组氨酸回复率与每平板肝蛋白浓度和每平板诱变剂浓度的函数关系。通过使用适当遗传杂交的后代,芳烃诱导的羟化酶活性似乎表现为常染色体显性性状,而3-甲基胆蒽在体外的诱变性似乎表现为累加性;这种明显的差异可能反映了由单加氧酶形成的酚类苯并[a]芘与诱变的3-甲基胆蒽代谢物相比的不同比例量。3-甲基胆蒽、6-氨基 Chrysene和2-乙酰氨基芴(而非苯并[a]芘)每分子细胞色素P1-450在体外的诱变性比每分子除P1450之外的一氧化碳结合细胞色素更高。还在体外研究了马来酸二乙酯(一种消耗肝脏中谷胱甘肽含量的化合物)和1,1,1-三氯丙烯-2,3-环氧化物(一种环氧水解酶(EC 4.2.1.63)抑制剂)。马来酸二乙酯,尤其是1,1,1-三氯丙烯-2,3-环氧化物,增加了苯并[a]芘的诱变性,而3-甲基胆蒽、6-氨基 Chrysene或2-乙酰氨基芴在体外活化成诱变剂时没有增加。当使用来自苯巴比妥处理小鼠的肝匀浆时,马来酸二乙酯和1,1,1-三氯丙烯-2,3-环氧化物均导致2-乙酰氨基芴在体外的诱变性降低。