Effect of xenobiotic estrogens and structurally related compounds on 2-hydroxylation of estradiol and on other monooxygenase activities in rat liver.
Effect of xenobiotic estrogens and structurally related compounds on 2-hydroxylation of estradiol and on other monooxygenase activities in rat liver.
复制标题
异生雌激素和结构相关化合物对雌二醇 2-羟基化和大鼠肝脏中其他单加氧酶活性的影响。
DOI：
10.1016/0006-2952(83)90618-4
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发表时间：
1983
影响因子：
5.8
通讯作者：
Kupfer,D
中科院分区：
文献类型：
--
作者：
Bulger,WH;Kupfer,D
先前的研究表明，给予几天的1-邻氯苯基对氯苯基三氯乙烷（雌激素DDT衍生物）或他莫昔芬（抗雌激素），但不是2，2-双-对氯苯基二氯乙烯（非雌激素），对卵巢切除的雌性大鼠，随后给予雌二醇显著降低了子宫鸟氨酸脱羧酶（ODC）的诱导作用。W.H. Bulger和D. Kupfer，Archs Biochem.Bioprotein.182，138（1977）]。本研究探讨了o，p′DDT和他莫昔芬对ODC诱导的抑制是否可能是由于肝单加氧酶系统增强雌二醇的羟基化。此外，其他雌激素和非雌激素外源性物质对雌二醇代谢（2-羟基化）的主要途径的影响进行了检查。用o，p′DDT或p，p′DDE处理去卵巢大鼠，可诱导肝脏雌二醇2-羟基化，并增加几种底物的脱甲基酶活性。肝单加氧酶的诱导剂甲酮（雌激素）和灭蚁灵（非雌激素）的给药也增加了雌二醇的2-羟基化。为了进行比较，还研究了经典雌激素（雌二醇和己烯雌酚）和抗雌激素（他莫昔芬）以及单加氧酶活性诱导剂（苯巴比妥和3-甲基胆蒽）给药对雌二醇-2-羟基化的影响。用雌二醇或己烯雌酚处理卵巢切除和肾上腺切除的雌性大鼠或完整雌性大鼠对雌二醇-2-羟基化没有影响。同样，他莫昔芬也没有改变雌二醇-2-羟基化的速率。用3-甲基胆蒽处理BMX/ADX大鼠不影响雌二醇-2-羟基化的速率。相比之下，用苯巴比妥处理的雌性或完整雄性大鼠表现出雌二醇-2-羟化酶活性的诱导。在上述研究中，仅发现2-羟基雌二醇;没有证据表明在雌二醇的其他位点形成羟基化的初级代谢产物。目前的研究结果排除了先前观察到的o，p′DDT或他莫昔芬预处理抑制雌二醇介导的ODC诱导的可能性（见上文引用的文章），这是由于肝脏单加氧酶增强了雌二醇的羟基化。此外，得出的结论是，诱导肝微粒体雌二醇-2-羟化酶活性的能力与给定化合物的雌激素（或抗雌激素）特性之间没有相关性。
Previous study demonstrated that the administration for several days of 1-(o-chlorophenyl)-1-(p-chlorophenyl)-2,2,2-trichloroethane (o,p′DDT) (estrogenic DDT derivative) or of tamoxifen (antiestrogen), but not of 2,2-bis-(p-chlorophenyl)-1,1-dichloroethylene (p,p′DDE) (nonestrogen), to ovariectomized female rats dramatically diminished the induction of uterine ornithine decarboxylase (ODC) by subsequently administered estradiol [W.H. Bulger and D. Kupfer,Archs Biochem. Biophys.182, 138 (1977)]. The present investigation examines whether the inhibition of ODC induction byo,p′DDT and tamoxifen may have been due to enhanced hydroxylation of estradiol by the hepatic monooxygenase system. Additionally, the effects of other estrogenic and nonestrogenic xenobiotics on the major route of estradiol metabolism (2-hydroxylation) were examined. Treatment of ovariectomized (ovex) rats witho,p′DDT orp,p′DDE caused induction of hepatic estradiol-2-hydroxylation and increased demethylase activities of several substrates. Administration of Kepone (estrogenic) and Mirex (nonestrogenic), both inducers of hepatic monooxygenase, also increased 2-hydroxylation of estradiol. For comparative purposes, the effects on estradiol-2-hydroxylation of administration of classical estrogens (estradiol and diethylstilbestrol) and antiestrogen (tamoxifen) and inducers of monooxygenase activity (phenobarbital and 3-methylcholanthrene) were also studied. Treatment of ovariectomized and adrenalectomized (ovex/adx) or intact female rats with estradiol or ovex/adx animals with diethylstilbestrol had no effect on estradiol-2-hydroxylation. Similarly, tamoxifen did not alter the rate of estradiol-2-hydroxylation. The treatment of ovex/adx rats with 3-methylcholanthrene did not affect the rate of estradiol-2-hydroxylation. By contrast, ovex/adx female or intact male rats treated with phenobarbital exhibited induction of estradiol-2-hydroxylase activity. In the above studies only 2-hydroxy-estradiol was found; there was no evidence for the formation of primary metabolites hydroxylated at other sites on estradiol. The current findings exclude the possibility that the previously observed inhibition of estradiol-mediated induction of ODC by pretreatment witho,p′DDT or tamoxifen (see article cited above) was due to enhanced hydroxylation of estradiol by liver monooxygenases. Also, it was concluded that there is no correlation between the ability to induce hepatic microsomal estradiol-2-hydroxylase activity and estrogenic (or antiestrogenic) properties of a given compound.