Benzo(e)pyrene [B(e)P], a weakly carcinogenic
polycyclic aromatic hydrocarbon, modifies
tumor induction in mouse skin and the induction of mutation in mammalian cells by carcinogenic
hydrocarbons. To determine how B(e)P alters the activation of the
carcinogen 7,12-dimethylbenz(a)anthracene (DMBA) to
DNA-binding metabolites, the
hydrocarbon-
DNA adducts formed in Syrian hamster embryo cell cultures were analyzed after 24, 48, or 72 h of exposure to 0.1 microgram DMBA/ml medium in the presence of various doses of B(e)P. The total binding of DMBA to
DNA was inhibited 3- to 4-fold by high doses of B(e)P, while the binding of DMBA to
DNA was increased by low doses of B(e)P at 48 and 72 h of exposure. The amounts of the three major adducts tentatively identified as anti-DMBA-3,4-diol-1,2-epoxide (DMBADE):
deoxyguanosine, syn - DMBADE:
deoxyadenosine (dAdo), and anti-DMBADE:dAdo decreased in the presence of 1.5 micrograms B(e)P/ml. In contrast, exposure to low doses of B(e)P, 0.1 and 0.3 microgram/ml medium, resulted in an increase in the amount of both anti-DMBADE:deoxyribonucleoside adducts and a decrease in the amount of syn-DMBADE:deoxyribonucleoside adduct present after 48 and 72 h of exposure. Thus, low doses of B(e)P specifically enhanced the formation of anti-DMBA-diol-
epoxide:deoxyribonucleoside adducts, and this resulted in an increase in the total amount of DMBA bound to
DNA. High doses of B(e)P resulted in a decrease in the formation of all DMBA:
DNA adducts and consequently a decrease in the total binding of DMBA to
DNA. The amount of DMBA bound to
DNA in cultures exposed to a higher dose of DMBA, 0.2 microgram DMBA/ml medium, for 48 h decreased in the presence of both low and high concentrations of B(e)P. This decrease resulted from a reduction in the formation of all three major DMBA-
DNA adducts as the dose of B(e)P increased, but the decrease was larger for the syn-DMBADE:dAdo adduct than for the anti-DMBADE:
deoxyguanosine and :dAdo adducts. These results demonstrate that the effects of B(e)P on the metabolic activation of DMBA depend upon both the ratio of B(e)P:DMBA and the dose of DMBA. The ability of B(e)P to alter the stereochemical selectivity of activation of DMBA as well as the total amount of activated metabolites also suggests that the ratio of B(e)P:DMBA may be an important factor in B(e)P-induced modifications of the induction of
biological effects by DMBA.