Induction of nuclear catechol-O-methyltransferase by estrogens in hamster kidney: implications for estrogen-induced renal cancer.
Induction of nuclear catechol-O-methyltransferase by estrogens in hamster kidney: implications for estrogen-induced renal cancer.
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雌激素在仓鼠肾脏中诱导核儿茶酚-O-甲基转移酶：对雌激素诱导的肾癌的影响。
DOI：
10.1093/carcin/19.7.1307
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发表时间：
1998
期刊：
影响因子：
4.7
通讯作者：
Creveling,CR
中科院分区：
文献类型：
--
作者：
Weisz,J;Fritz-Wolz,G;Clawson,GA;Benedict,CM;Abendroth,C;Creveling,CR
儿茶酚雌激素通过在邻苯二酚和苯醌雌激素之间的氧化还原循环过程中产生的活性氧物种和可形成净化加合物的喹酮雌激素介导的DNA损伤而被认为有助于癌症的发生。上述假说主要基于对初级雌激素处理的仓鼠肾皮质发生癌症的研究：仓鼠肾脏可以催化雌激素的2-和4-羟化并支持其氧化还原循环，而雌激素处理的仓鼠肾脏显示出氧化细胞和DNA损伤的证据。在此，我们用免疫细胞化学的方法来验证这样一种假设，即雌二醇或炔雌二醇可在金黄地鼠的肾皮质中诱导儿茶酚-O-甲基转移酶(COMT)，这种酶可以防止儿茶酚类雌激素氧化成它们的苯醌衍生物。在对照仓鼠肾脏中，COMT定位于近曲小管上皮细胞的胞浆中，主要位于雌激素诱发肿瘤发生的延髓旁区域。雌激素治疗2-4周后，近曲小管上皮细胞中可见COMT，许多细胞也表现出强烈的核COMT免疫反应。雌二醇诱导的肾癌COMT阴性，但被胞浆和核免疫染色的小管包围。免疫印迹分析表明，核相关的COMT是该酶的可溶性形式。通过逆转录-聚合酶链式反应扩增，仓鼠肾脏COMT被证明缺乏人类COMT中可能存在的核定位信号序列。免疫细胞化学显示，在雌激素处理的金黄地鼠近曲小管中，第二相酶CuZn-超氧化物歧化酶(CuZnSOD)仍保持在核外，这表明COMT进入细胞核是有选择性的。这一发现与雌激素诱导癌症的儿茶酚/苯二酚雌激素假说一致，而雌激素治疗后酶移位到细胞核表明，这是对儿茶酚亲电产物对基因组威胁的反应。
Catecholestrogens are postulated to contribute to carcinogenesis by causing DNA damage mediated by reactive oxygen species generated during redox cycling between catechol and quinone estrogens, and by quinone estrogens that can form depurinating adducts. The above hypothesis is based principally on studies of the cancers that develop in renal cortex of hamsters treated with primary estrogens: Hamster kidney can catalyze 2- and 4-hydroxylation of estrogens and support their redox cycling, and the kidneys of estradiol-treated hamsters show evidence of oxidative cellular and DNA damage. Here we used immunocytochemisty to test the postulate that catechol-O-methyltransferase (COMT), the enzyme that can prevent oxidation of catecholestrogens to their quinone derivatives, would be induced in renal cortex of hamsters treated with estradiol or ethinyl estradiol. In kidneys of control hamsters, COMT was localized in cytoplasm of epithelial cells of proximal convoluted tubules, predominantly in the juxtamedullary region where the estrogen-induced cancers arise. After 2- or 4-weeks of treatment with either estrogen, COMT was seen in epithelial cells of proximal convoluted tubules throughout the cortex, and many cells also showed intense nuclear COMT immunoreactivity. Estradiol-induced renal cancers were negative for COMT, but were surrounded by tubules with intense cytoplasmic and nuclear immunostaining. The nucleus-associated COMT was shown by immunoblot analysis to be the soluble form of the enzyme. Using reverse transcription-polymerase chain reaction amplification, hamster kidney COMT was shown to lack the putative nuclear localization signal sequence present in human COMT. A second phase II enzyme, CuZn-superoxide dismutase (CuZnSOD), was shown by immunocytochemistry to remain extranuclear in proximal convoluted tubules of estrogen-treated hamsters, which indicates entry of COMT into the nucleus to be selective. The findings are consistent with the catechol/quinone estrogen hypothesis of estrogen-induced cancer, while the translocation of the enzyme to the nucleus following estrogen treatment suggests a response to a threat to the genome by electrophilic products of catechols.