Wong D C, Fong W P, Lee S S, Kong Y C, Cheng K F, Stone G
Department of Biochemistry, The Chinese University of Hong Kong, Shatin.
Eur J Pharmacol. 1998 Nov 27;362(1):87-93. doi: 10.1016/s0014-2999(98)00742-0.
Estrogen can be hydroxylated at both 2- and 16alpha-positions. These two reactions are mutually exclusive. The 2-hydroxylated estrogen is relatively inactive compared with the 16alpha-derivative; hence, one approach in anti-estrogenic therapy is to look for drugs that can induce the 2-hydroxylation pathway. In the present study, using Balb/c and C57B/6 mice as the animal models, the induction effect of several isoprenyl compounds on estradiol-2-hydroxylase and ethoxyresorufin-O-deethylase activities was studied. The compounds examined included 2'- and 3'-methylbutadienyl-indoles and their respective acid condensation products, isopropyl indolocarbazole and yuehchukene; positional isomers of indole carbinols and carboxyaldehydes, as well as 3-methylcholanthrene, the prototype inducer of cytochrome P450 1A1. Our results demonstrated that while all of them were capable of inducing cytochrome P450 1A1-mediated ethoxyresorufin-O-deethylase activity, only the 3' isomers could induce estradiol-2-hydroxylase activity. The induction of these two activities did not show any direct correlation, suggesting that cytochrome P450 1A1 was not the same enzyme catalyzing both ethoxyresorufin-O-deethylation and estradiol-2-hydroxylation. Nevertheless, both inductions were mediated by the aryl hydrocarbon receptor. Among the compounds tested, yuehchukene showed competitive binding to estrogen receptor. This, together with the induction of estradiol-2-hydroxylase activity, may account for the anti-estrogenic effect of yuehchukene.
雌激素可在2位和16α位发生羟基化。这两种反应相互排斥。与16α - 衍生物相比，2 - 羟基化雌激素相对无活性；因此，抗雌激素治疗的一种方法是寻找能够诱导2 - 羟基化途径的药物。在本研究中，以Balb/c和C57B/6小鼠作为动物模型，研究了几种异戊二烯基化合物对雌二醇 - 2 - 羟化酶和乙氧异羟肟酸 - O - 脱乙基酶活性的诱导作用。所检测的化合物包括2' - 和3' - 甲基丁二烯基 - 吲哚及其各自的酸缩合产物、异丙基吲哚咔唑和月腺大戟烯；吲哚甲醇和羧醛的位置异构体，以及细胞色素P450 1A1的原型诱导剂3 - 甲基胆蒽。我们的结果表明，虽然它们都能够诱导细胞色素P450 1A1介导的乙氧异羟肟酸 - O - 脱乙基酶活性，但只有3'异构体能够诱导雌二醇 - 2 - 羟化酶活性。这两种活性的诱导没有显示出任何直接相关性，表明细胞色素P450 1A1不是催化乙氧异羟肟酸 - O - 脱乙基化和雌二醇 - 2 - 羟基化的同一种酶。然而，这两种诱导均由芳烃受体介导。在所测试的化合物中，月腺大戟烯显示出与雌激素受体的竞争性结合。这一点，连同雌二醇 - 2 - 羟化酶活性的诱导，可能解释了月腺大戟烯的抗雌激素作用。
