Conney A H, Chang R L, Cui X X, Schiltz M, Yagi H, Jerina D M, Wei S J
Department of Chemical Biology, College of Pharmacy, Rutgers, the State University of New Jersey, Piscataway 08854-8020, USA.
Adv Exp Med Biol. 2001;500:697-707. doi: 10.1007/978-1-4615-0667-6_102.
Chinese hamster V79 cells were exposed to a high or low concentration of the highly carcinogenic (R,S,S,R) or the less active (S,R,R,S) bay- or fjord-region diol epoxides of benzo[a]pyrene, benzo[c]phenanthrene or dibenz[c,h]acridine. Independent 8-azaguanine-resistant clones were isolated, and base substitutions at the hypoxanthine (guanine) phosphoribosyltransferase (hprt) locus were determined. For the three (R,S,S,R) diol epoxides studied, the proportion of mutations at AT base pairs increased as the concentration of diol epoxide decreased. Concentration-dependent differences in the mutational profile were not observed, however, for the three (S,R,R,S) diol epoxides. In studies, with V-H1 cells (a DNA repair deficient variant of V79 cells), a concentration-dependent difference in the profile of mutations for the (R,S,S,R) diol epoxide of benzo[a]pyrene was not observed. These results suggest that concentration-dependent differences in the mutational profile are dependent on an intact DNA repair system. In additional studies, we initiated mouse skin with a high or low dose of benzo[a]pyrene and promoted the mice for 26 weeks with 12-O-tetradecanoylphorbol-13-acetate. Papillomas were examined for mutations in the c-Ha-ras proto-oncogene. Dose-dependent differences in the profile of c-Ha-ras mutations in the tumors were observed. In summary, (i) dose-dependent differences in mutational profiles at the hprt locus were observed in Chinese hamster V79 cells treated with several highly mutagenic and carcinogenic (R,S,S,R) bay- or fjord-region diol epoxides but not with their less active (S,R,R,S) diol epoxide enantiomers, (ii) a dose-dependent difference in the mutational profile was not observed for the (R,S,S,R) diol epoxide of benzo[a]pyrene in a DNA-repair defective V79 cell line, and (iii) a dose-dependent difference in the mutational profile in the c-Ha-ras proto-oncogene was observed in tumors from mice treated with a high or low dose of benzo[a]pyrene.
将中国仓鼠V79细胞暴露于高浓度或低浓度的高致癌性（R,S,S,R）或活性较低的（S,R,R,S）苯并[a]芘、苯并[c]菲或二苯并[c,h]吖啶的湾区或峡湾区二醇环氧化物中。分离出独立的8-氮杂鸟嘌呤抗性克隆，并确定次黄嘌呤（鸟嘌呤）磷酸核糖基转移酶（hprt）基因座处的碱基替换。对于所研究的三种（R,S,S,R）二醇环氧化物，随着二醇环氧化物浓度的降低，AT碱基对处的突变比例增加。然而，对于三种（S,R,R,S）二醇环氧化物，未观察到突变谱中的浓度依赖性差异。在对V-H1细胞（V79细胞的一种DNA修复缺陷变体）的研究中，未观察到苯并[a]芘的（R,S,S,R）二醇环氧化物突变谱中的浓度依赖性差异。这些结果表明，突变谱中的浓度依赖性差异取决于完整的DNA修复系统。在另外的研究中，我们用高剂量或低剂量的苯并[a]芘启动小鼠皮肤，并用地塞米松12-O-十四烷酰佛波醇-13-乙酸酯促进小鼠26周。检查乳头瘤中c-Ha-ras原癌基因的突变。观察到肿瘤中c-Ha-ras突变谱的剂量依赖性差异。总之，（i）在用几种高致突变性和致癌性的（R,S,S,R）湾区或峡湾区二醇环氧化物处理的中国仓鼠V79细胞中，观察到hprt基因座处突变谱的剂量依赖性差异，但用其活性较低的（S,R,R,S）二醇环氧化物对映体处理时未观察到，（ii）在DNA修复缺陷的V79细胞系中，未观察到苯并[a]芘的（R,S,S,R）二醇环氧化物突变谱的剂量依赖性差异，并且（iii）在用高剂量或低剂量苯并[a]芘处理的小鼠肿瘤中，观察到c-Ha-ras原癌基因中突变谱的剂量依赖性差异。
