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

致癌的多环芳烃苯并[α]芘， 7，12-二甲基苯并[α]蒽、二苯并[α]芘和一些 它们的代谢产物形成两种类型的DNA加合物， 在DNA或脱嘌呤加合物中， 糖苷键，留下脱嘌呤位点。 脱嘌呤加合物和 随后产生的脱嘌呤位点的错误复制起主要作用， 小鼠皮肤乳头状瘤中c-Harvey（H）-ras癌基因突变的作用 由上述PAH引起。 为了确认和扩展 脱嘌呤加合物和致癌突变，我们建议研究其他 选择的PAH、衍生物和代谢物。 这些研究旨在 获得进一步的证据表明，形成的脱嘌呤加合物发挥作用， 在PAH引发肿瘤中起关键作用。 我们还提出雌激素 代谢产物，即儿茶酚雌激素醌（CE-Q），是内源性肿瘤 引发剂，因为它们中的一些通过与 DNA. 儿茶酚类雌激素（CE）是雌激素的主要代谢产物 雌酮（E1）和17 β-雌二醇（F2），可以被激活到最终 致癌形式，即CE-3，4-Q。 CE-3，4-Q与DNA反应形成 脱嘌呤N7 Gua加合物将构成肿瘤的起始步骤， 雌激素诱导。 据推测，由于失去了蛋白质， 这些N7瓜加合物可能被错误复制，导致致癌突变。 为了确定脱嘌呤CE-DNA加合物在致癌作用中的作用， 建议测定肾脏和尿液中的脱嘌呤DNA加合物 雄性仓鼠肾脏样品中的稳定DNA加合物 （易受E1和E2诱导的肾肿瘤影响）接受CE-Q或 它们的前体，并将这些结果与类似的 处理的雄性大鼠（对E1和E2诱导的肾肿瘤难治）。 这些 研究将得到儿茶酚类类似研究的支持， 合成非甾体雌激素的醌类， 己烷雌酚。 从这些研究中，我们期望获得令人信服的证据， (1)脱嘌呤DNA加合物通过产生 致癌突变和（2）CE-2，4-Q是内源性肿瘤引发剂， 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.