Dose-dependent differences in the profile of mutations induced by carcinogenic (R,S,S,R) bay- and fjord-region diol epoxides of polycyclic aromatic hydrocarbons.
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.
Conney
A H
AH
Department of Chemical Biology, College of Pharmacy, Rutgers, the State University of New Jersey, Piscataway 08854-8020, USA.
Chang
R L
RL
Cui
X X
XX
Schiltz
M
M
Yagi
H
H
Jerina
D M
DM
Wei
S J
SJ
D000166:Acridines / Q000009:adverse effects* / Q000494:pharmacology; D019943:Amino Acid Substitution; D000818:Animals; D001483:Base Sequence; D018383:Bay-Region, Polycyclic Aromatic Hydrocarbon; D001564:Benzo(a)pyrene / Q000009:adverse effects / Q000494:pharmacology; D002273:Carcinogens / Q000009:adverse effects* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004852:Epoxy Compounds; D011905:Genes, ras; D006801:Humans; D007041:Hypoxanthine Phosphoribosyltransferase / Q000235:genetics*; D008969:Molecular Sequence Data; D016296:Mutagenesis; D010616:Phenanthrenes / Q000009:adverse effects* / Q000494:pharmacology; D011084:Polycyclic Aromatic Hydrocarbons / Q000009:adverse effects / Q000494:pharmacology; D000090063:Proto-Oncogene Mas; D012878:Skin Neoplasms / Q000188:drug therapy / Q000235:genetics
D000166:Acridines; D002273:Carcinogens; D004852:Epoxy Compounds; C000715470:MAS1 protein, human; D010616:Phenanthrenes; D011084:Polycyclic Aromatic Hydrocarbons; D000090063:Proto-Oncogene Mas; C460375:dibenz(c,h)acridine; D001564:Benzo(a)pyrene; D007041:Hypoxanthine Phosphoribosyltransferase; C002615:benzo(c)phenanthrene