The O-methylation of 4-hydroxyestradiol is inhibited by 2-hydroxyestradiol: implications for estrogen-induced carcinogenesis.
The O-methylation of 4-hydroxyestradiol is inhibited by 2-hydroxyestradiol: implications for estrogen-induced carcinogenesis.
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4-羟基雌二醇的 O-甲基化被 2-羟基雌二醇抑制：对雌激素诱导的致癌作用的影响。
DOI：
10.1093/carcin/11.3.459
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发表时间：
1990
期刊：
影响因子：
4.7
通讯作者：
Liehr,JG
中科院分区：
文献类型：
--
作者：
Roy,D;Weisz,J;Liehr,JG
儿茶酚-O-甲基转移酶催化的儿茶酚类雌激素的O-甲基化为这些类固醇的快速代谢清除提供了一条主要途径。尽管2-和4-羟基儿茶酚雌激素(2-和4-OH-CE)对酶有相似的表观亲和力，但4-羟基雌二醇(4-OH-E_2)的代谢清除率明显低于2-羟基雌二醇。为了确定这一明显矛盾的原因，我们考察了其他儿茶酚雌激素或它们的O-甲基醚是否会影响4-OH-E2的甲基化效率。反应的最适pH值为8.5，4-甲氧基雌二醇与4-羟基雌二醇3-甲基醚的摩尔比为2.6。2-羟基雌二醇(2-OH-E_2)可抑制4-OH-E_2(明显为Km10μM)的甲基化，但不能被2-或4-甲氧基雌激素所抑制。2-OH-E2改变了Km、Vmax和4-OH-E2的甲基化斜率，表现为混合抑制。截距1/V‘max对2-OH-E2浓度的抑制常数和斜率对2-OH-E2浓度的抑制常数分别为35和5.7μM。2-OH-E2对4-OH-E2甲基化的抑制作用随pH升高而增强。在雌激素致癌作用的靶组织中，如大鼠垂体、仓鼠肾脏或小鼠子宫中，2-和4-OH-CE的生成量几乎相等，4-OH-CE的甲基化失活可能受到阻碍。因此，4-OH-E2仍可作为氧化还原循环、活性自由基的产生和DNA损伤的底物。
O-Methylation of catecholestrogens catalyzed by catechol-O-methyltransferase provides a major route for the rapid metabolic clearance of these steroids. However, the metabolic clearance rate of 4-hydroxyestradiol (4-OH-E2) is considerably lower than that of 2-hydroxyestradiol, although 2- and 4-hydroxycatecholestrogens (2- and 4-OH-CE) have similar apparent affinities for the enzyme. To determine the reason for this apparent paradox we have examined whether the efficiency ofO-methylation of 4-OH-E2could be affected by other catecholestrogens or theirO-methyl ethers. The ratio of 4-methoxyestradiol:4-hydroxyestradiol 3-methyl ether was 2.6 at pH 8.5, the pH optimum for the reaction. TheO-methylation of 4-OH-E2(apparentKm10 μM) was inhibited by 2-hydroxyestradiol (2-OH-E2) but not by 2- or 4-methoxyestrogens. The values forKm,Vmaxas well as the slope for the methylation of 4-OH-E2were altered by 2-OH-E2indicating a mixed inhibition. The inhibition constant for the intercept 1/V'maxversus 2-OH-E2concentrations and the inhibition constant for the slope versus 2-OH-E2concentrations were 35 and 5.7 μM, respectively. The inhibition ofO-methylation of 4-OH-E2by 2-OH-E2increased with the pH. In target tissues of the carcinogenic action of estrogens such as the rat pituitary, hamster kidney, or mouse uterus in which 2- and 4-OH-CE are both generated in almost equal amounts, the inactivation of 4-OH-CE byO-methylation may be impeded. Consequently, 4-OH-E2would remain available as substrate for redox cycling, generation of active radicals and DNA damage.