Catecholestrogen sulfation: Possible role in carcinogenesis
Catecholestrogen sulfation: Possible role in carcinogenesis
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DOI：
10.1006/bbrc.2002.6658
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发表时间：
2002-03-29
影响因子：
3.1
通讯作者：
Weinshilboum, RM
中科院分区：
文献类型：
--
作者：
Adjei, AA;Weinshilboum, RM
越来越多的证据支持这一假设，即雌激素可能是致癌物质，因为它们在生物转化后转化为遗传毒素，形成儿茶酚雌激素（CE）2-羟基雌酮（2-OHE 1），2-羟基雌酮（2-OHE 2），4-羟基雌酮（4-OHE 1）和4-羟基雌酮（4-OHE 2）。然后，CE可以进一步代谢形成醌，醌与DNA相互作用形成稳定的或脱嘌呤的加合物。这些事件可能被母体雌激素和/或CE的硫酸盐结合中断。我们着手确定CE是否可以作为硫酸盐缀合的底物，如果可以的话，那么在不断增长的人类磺基转移酶（SULT）亚型家族中，哪一种能够催化这些反应。我们测定了10种重组人SULT亚型的表观Km值，以及SULT 1A 1和SULT 1A 2的三种最常见的等位酶，2-OHE 1、2-OHE 2、4-OHE 1和4-OHE 2，以及内源性雌激素雌酮（E1）和17 β-雌二醇（E2）作为底物。除了SULT 1B 1、SULT 1C 1和SULT 4A 1之外，研究的所有人SULT均催化CE的硫酸盐缀合。SULT 1 E1对4-OHE 1、4-OHE 2、2-OHE 1和2-OHE 2的表观K-m值最低，分别为0.31、0.18、0.27和0.22 μ M。这些结果表明，SULT可以催化CE的硫酸盐结合，并且它们提高了这样的可能性，即由于常见的遗传多态性，雌激素和CE代谢途径中的个体差异可能是雌激素依赖性致癌的危险因素。(C)2002 Elsevier Science（美国）。
A growing body of evidence supports the hypothesis that estrogens can be carcinogens as a result of their conversion to genotoxins after biotransformation to form the catecholestrogens (CEs) 2-hydroxyestrone (2-OHE1), 2-hydroxyestradiol (2-OHE2), 4-hydroxyestrone (4-OHE1) and 4-hydroxyestradiol (4-OHE2). CEs can then undergo further metabolism to form quinones that interact with DNA to form either stable or depurinating adducts. These events could potentially be interrupted by the sulfate conjugation of both the parent estrogens and/or the CEs. We set out to determine whether CEs can serve as substrates for sulfate conjugation, and-if so-which of the growing family of human sulfotransferase (SULT) isoforms are capable of catalyzing those reactions. We determined apparent K-m values for 10 recombinant human SULT isoforms, as well as the three most common allozymes for SULT1A1 and SULT1A2, with 2-OHE1, 2-OHE2, 4-OHE1, and 4-OHE2, and with the endogenous estrogens, estrone (E1) and 17beta-estradiol (E2), as substrates. With the exception of SULT1B1, SULT1C1, and SULT4A1, all of the human SULTs studied catalyzed the sulfate conjugation of CEs. SULT1E1 had the lowest apparent K-m values, 0.31, 0.18, 0.27, and 0.22 muM for 4-OHE1, 4-OHE2, 2-OHE1, and 2-OHE2, respectively. These results demonstrate that SULTs can catalyze the sulfate conjugation of CEs, and they raise the possibility that individual variation in this pathway for estrogen and CE metabolism as a result of common genetic polymorphisms could represent a risk factor for estrogen-dependent carcinogenesis. (C) 2002 Elsevier Science (USA).