7,12-Dimethylbenz[a]anthracene-DNA adducts in Sprague-Dawley and Long-Evans female rats: the relationship of DNA adducts to mammary cancer

Abstract

7,12-Dimethylbenz[a]anthracene (DMBA) is a powerful carcinogen to the mammary gland of the pubescent female Sprague-Dawley (S.D.) rat but is a much less potent inducer of mammary adenocarcinoma in the female Long-Evans (L.E.) rat of the same age. The livers of both strains are refractory to DMBA. The maximum levels of DMBA--DNA adducts formed, in both the mammary gland and liver following i.p. administration of [3H]DMBA (21 mumol) were significantly higher (p less than 0.01) in the resistant L.E. strain than the sensitive S.D. strain. Maximal levels of DMBA--DNA adducts were observed at approximately 48 h post administration of the hydrocarbon for both organs of both strains. For the S.D. animals no significant loss of adducts (relative to the 48 h maxima) was observed from either organ at the last time point (336 h). In contrast both organs of the L.E. strain showed some evidence of adduct removal. Analysis of the DMBA--deoxyribonucleoside adducts by h.p.l.c. following enzymatic hydrolysis of the purified DNA showed that A-ring diol-epoxide adducts of both DMBA and a major metabolite 7-hydroxymethyl-12-methylbenz[a]anthracene (7OHM-12MBA) were present in both organs from both strains. In both strains the levels of 7OHM-12MBA adducts were less, relative to the DMBA adducts, in the mammary gland than in the liver. With respect to specific adduct removal, L.E. animals removed approximately 70% of the identifiable adducts from the liver DNA in the 48 h to 336 h (12 d) time period. In contrast the S.D. animals showed no such capability for removing these adducts during this same time frame. These observations indicate that some factor(s) in addition to, or in conjunction with, the levels of DMBA--DNA adducts initially formed are responsible for the overall relative sensitivities of the S.D. and L.E. mammary gland to this hydrocarbon. One such parameter might be the relative propensity for specific adduct removal or the relative capacity of the two strains to repair DMBA-induced DNA damage.