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

致癌的多环芳烃(PAH)苯并[α]芘， 7，12-二甲基苯并[α]菲，二苯并[α-L]芘和一些 他们的代谢产物形成两种类型的DNA加合物，即稳定的加合物 脱氧核糖核酸或脱氧核糖核酸的加合物，这些加合物是通过水解脱氧核糖核酸 糖苷键，留下无嘌呤基位。去小便加合物和 随后的误复制产生的无嘌呤位点发挥了主要作用 C-Harvey(H)-ras癌基因突变在小鼠皮肤乳头状瘤中的作用 由上述多环芳烃诱导。以确认和扩展 提纯加合物和致癌突变，我们建议研究其他 精选的多环芳烃、衍生物和代谢物。这些研究旨在 获得进一步的证据表明，净化加合物的形成对 PAH在肿瘤发生中的关键作用。我们还建议雌激素 代谢产物，即邻苯二酚类雌激素醌(CE-Q)，是内源性肿瘤。 引发剂，因为它们中的一些通过与 DNA儿茶酚雌激素(CE)是雌激素的主要代谢物 雌酮(E1)和17β-雌二醇(F2)，可被激活至终极 致癌形式，即CE-3，4-Q。Ce-3，4-Q与DNA的反应生成 提纯N7Gua加合物将构成肿瘤的起始步骤 雌激素诱导。据推测，由于失去了 这些N7Gua加合物可能会被错误复制，导致致癌突变。 为了确定提纯CE-DNA加合物在致癌中的作用 肾和尿液中脱氧核糖核酸加合物测定的建议 雄性仓鼠肾脏标本及其稳定的DNA加合物 (易受E_1和E_2诱导的肾肿瘤)用CE-Q或 并将这些结果与类似的 处理的雄性大鼠(对E_1和E_2诱导的肾肿瘤无效)。这些 这项研究将得到儿茶酚和 合成非甾体雌激素己烯雌酚和己烯雌酚中的喹酮类化合物 己烯雌酚。从这些研究中，我们期望得到令人信服的证据 (1)提纯DNA加合物通过生成 癌基因突变和(2)CE-2，4-Q是内源性肿瘤启动剂 可能是诱发多种人类癌症的罪魁祸首。

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.