Molecular origin of cancer: Catechol estrogen-3,4-quinones as endogenous tumor initiators
Molecular origin of cancer: Catechol estrogen-3,4-quinones as endogenous tumor initiators
复制标题
DOI：
10.1073/pnas.94.20.10937
复制
发表时间：
1997-09-30
影响因子：
11.1
通讯作者：
Rogan, EG
中科院分区：
文献类型：
--
作者：
Cavalieri, EL;Stack, DE;Rogan, EG
癌症是一种以癌基因和抑癌基因等关键基因突变为起点的疾病。我们对致癌芳烃的研究表明，脱嘌呤的烃-DNA加合物产生在小鼠皮肤乳头状瘤中发现的致癌突变（Proc. Natl. Acad. Sci. USA 92：10422，1995）。这些突变是由于脱嘌呤加合物丢失导致的未修复脱嘌呤位点的错误复制而引起的。这种关系使我们假设，雌酮（E-1）和雌二醇（E-2）的致癌4-羟基儿茶酚雌激素（CE）氧化为儿茶酚雌激素-3，4-醌（CE-3，4-Q）导致亲电中间体共价结合DNA形成脱嘌呤加合物。在关键基因中产生的脱嘌呤位点可以产生可能引发各种人类癌症的突变。非致癌的2-羟基CE被氧化为CE-2，3-Q，仅形成稳定的DNA加合物。如本文所报道的，CE-3，4-Q在体外与DNA结合，形成脱嘌呤加合物4-OHE 1（E-2）-1（α，β）-N7 Gua，其浓度为59-213 μ mol/mol DNA-磷酸，而稳定加合物的水平为0.1 μ mol/mol DNA-磷酸。在雌性Sprague-Dawley大鼠的四个乳腺乳头内注射E-2- 3，4-Q（200 nmol），乳腺组织含有2.3 μ mol 4-OHE 2 -1（α，β）-N7 Gua/mol DNA-磷酸盐。当4-OHE 1（E-2）被辣根过氧化物酶、乳过氧化物酶或细胞色素P450激活时，形成87-440 μ mol的4-OHE 1（E-2）-1（α，β）-N7 Gua。用4-OHE 2处理后，大鼠乳腺组织含有1.4 μ mol加合物/mol DNA-磷酸。在每种情况下，稳定加合物的水平可以忽略不计。这些结果，由其他数据补充，强烈支持CE-3，4-Q是内源性肿瘤引发剂的假设。
Cancer is a disease that begins with mutation of critical genes: oncogenes and tumor suppressor genes. Our research on carcinogenic aromatic hydrocarbons indicates that depurinating hydrocarbon-DNA adducts generate oncogenic mutations found in mouse skin papillomas (Proc. Natl. Acad. Sci. USA 92:10422, 1995). These mutations arise by mis-replication of unrepaired apurinic sites derived from the loss of depurinating adducts. This relationship led us to postulate that oxidation of the carcinogenic 4-hydroxy catechol estrogens (CE) of estrone (E-1) and estradiol (E-2) to catechol estrogen-3,4-quinones (CE-3, 4-Q) results in electrophilic intermediates that covalently bind to DNA to form depurinating adducts. The resultant apurinic sites in critical genes can generate mutations that may initiate various human cancers. The noncarcinogenic 2-hydroxy CE are oxidized to CE-2,3-Q and form only stable DNA adducts. As reported here, the CE-3,4-Q were bound to DNA in vitro to form the depurinating adduct 4-OHE1(E-2)-1(alpha,beta)-N7Gua at 59-213 mu mol/mol DNA-phosphate whereas the level of stable adducts was 0.1 mu mol/mol DNA-phosphate. In female Sprague-Dawley rats treated by intramammillary injection of E-2-3,4-Q (200 nmol) at four mammary glands, the mammary tissue contained 2.3 mu mol 4-OHE2-1(alpha,beta)-N7Gua/molDNA-phosphate. When 4-OHE1(E-2) were activated by horseradish peroxidase, lactoperoxidase, or cytochrome P450, 87-440 mu mol of 4-OHE1(E-2)-1(alpha,beta)-N7Gua was formed, After treatment with 4-OHE2, rat mammary tissue contained 1.4 mu mol of adduct/mol DNA-phosphate. In each case, the level of stable adducts was negligible. These results, complemented by other data, strongly support the hypothesis that CE-3,4-Q are endogenous tumor initiators.