DNA ADDUCTS AND APURINIC SITES--THE ESTROGEN-PAH CONNECTION

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The carcinogenic polycyclic aromatic hydrocarbons (PAH) benzo[alpha]pyrene, 7,12-dimethylbenz[alpha]anthracene, dibenzo[alpha l)pyrene and some of their metabolites form two types of DNA adducts, stable adducts that remain in DNA or depurinating adducts that are lost from DNA by hydrolysis of the glycosidic bond, leaving apurinic sites. Depurinating adducts and subsequent mis-replication of the apurinic sites generated play the major role in mutating the c-Harvey (H)-ras oncogene in mouse skin papillomas induced by the above PAH. To confirm and extend the correlation between depurinating adducts and oncogenic mutations, we propose to study other selected PAH, derivatives and metabolites. These studies are designed to gain further evidence that formation of depurinating adducts plays a critical role in tumor initiation by PAH. We also propose that estrogen metabolites, namely catechol estrogen quinones (CE-Q), are endogenous tumor initiators because some of them form depurinating adducts by reaction with DNA. Catechol estrogens (CE) are major metabolites of the estrogens estrone (E1) and 17beta-estradiol (F2) that can be activated to ultimate carcinogenic forms, namely CE-3,4-Q. Reaction of CE-3,4-Q with DNA to form depurinating N7Gua adducts would constitute the initiating step of tumor induction by estrogens. Presumably the apurinic sites generated by loss of those N7Gua adducts can be mis-replicated, leading to oncogenic mutations. To determine the role of depurinating CE-DNA adducts in carcinogenesis we propose to determine the depurinating DNA adducts in kidney and urine samples and the stable DNA adducts in kidney samples from male hamsters (susceptible to E1- and E2- induced renal tumors) treated with CE-Q or their precursors and compare these results with those from similarly treated male rats (refractory to E1- and E2- induced renal tumors). These studies will be supported by similar studies with the catechols and quinones of the synthetic nonsteroidal estrogens diethylstilbestrol and hexestrol. From these studies we expect to gain convincing evidence that (1) depurinating DNA adducts lead to tumor initiation by generating oncogenic mutations and (2) CE-2,4-Q are endogenous tumor initiators that could be the culprit in the induction of a variety of human cancers.