Relationship between benzo(a)pyrene-induced DNA base modification and frequency of reverse mutations in mutant strains of Salmonella typhimurium.
Salmonella typhimurium cells (TA98 and TA100) were incubated with [3H]benzo(a)pyrene ([3H]BP) and induced rat liver microsomes. The BP-induced cytotoxicity and His+ reverse-mutation frequencies were determined, and bacterial DNA hydrolysates were chromatographed on Sephadex LH-20. Analysis indicated three principal DNA adducts formed from two diastereoisomeric BP diol-epoxides and a 9-hydroxy-benzo(a)pyrene metabolite. An 8.6-fold increase in TA100 cell concentration in the microsome incubation was paralleled by a 7.2-fold decrease in total adducts per cell and a 7.4-fold decrease in mutation frequency. Separate TA98 incubations were titrated with increasing concentrations of [3H](+/-)-7 beta, 8 alpha-dihydroxy-9 alpha, 10 alpha-epoxy-7,8,9,10-tetrahydrobenzo(a)pyrene ([3H]anti BP diol-epoxide), [3H](+/-)-7 beta, 8 alpha-dihydroxy-9 beta, 10 beta-epoxy-7,8,9,10-tetrahydrobenzo(a)pyrene [3H]syn BP diol-epoxide), or [3H]9-hydroxybenzo(a)pyrene. Linear, nonsaturated increases in DNA adduct levels were seen up to the highest observed concentrations of 4.00 microM BP diol-epoxide or 6.00 microM 9-hydroxybenzo(a)pyrene in both TA98 and TA100 cells. The increasing adduct levels were accompanied by linearly increasing mutation frequencies. At equivalent concentrations of the two DP diol-epoxides, an average of 8.2-fold more base substitution mutations (TA100) were seen than frameshift mutations (TA98). The results also indicate significant differences in absolute mutagenic efficiency (mutation frequency/unit modified DNA) between these three covalent DNA ligands (TA98, syn BP diolepoxide greater than 9-hydroxy-4,5-epoxy-benzo(a)pyrene greater than anti BP diol-epoxide; TA100, 9-hydroxy-4,5-epoxy-benzo(a)pyrene greater than syn BP diol-epoxide greater than anti BP diol-epoxide).
D000818:Animals; D001482:Base Composition / Q000187:drug effects; D001564:Benzo(a)pyrene; D001580:Benzopyrenes / Q000633:toxicity*; D004269:DNA, Bacterial / Q000378:metabolism*; D003853:Deoxyribonucleosides / Q000378:metabolism; D008297:Male; D008748:Methylcholanthrene / Q000494:pharmacology; D008862:Microsomes, Liver / Q000187:drug effects; D009153:Mutagens; D009154:Mutation / Q000187:drug effects; D051381:Rats; D012486:Salmonella typhimurium / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism
D001580:Benzopyrenes; D004269:DNA, Bacterial; D003853:Deoxyribonucleosides; D009153:Mutagens; D001564:Benzo(a)pyrene; D008748:Methylcholanthrene