Bulger W H, Kupfer D
Biochem Pharmacol. 1983 Mar 15;32(6):1005-10. doi: 10.1016/0006-2952(83)90618-4.
Previous study demonstrated that the administration for several days of 1-(o-chlorphenyl)-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 by o,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 with o,p'DDT or p,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-hydroxyestradiol 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 with o,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.
先前的研究表明，给去卵巢的雌性大鼠连续数天施用1-（邻氯苯基）-1-（对氯苯基）-2,2,2-三氯乙烷（o,p'DDT）（具有雌激素活性的滴滴涕衍生物）或他莫昔芬（抗雌激素药物），而非2,2-双-（对氯苯基）-1,1-二氯乙烯（p,p'DDE）（无雌激素活性），会显著减弱随后施用的雌二醇对子宫鸟氨酸脱羧酶（ODC）的诱导作用[W. H. 布尔格和D. 库普弗，《生物化学与生物物理学文献》，182, 138 (1977)]。本研究探讨了o,p'DDT和他莫昔芬对ODC诱导作用的抑制是否可能是由于肝单加氧酶系统对雌二醇的羟基化作用增强所致。此外，还研究了其他具有雌激素活性和无雌激素活性的外源性化学物质对雌二醇主要代谢途径（2-羟基化）的影响。用o,p'DDT或p,p'DDE处理去卵巢（ovex）大鼠会诱导肝雌二醇-2-羟基化，并增加几种底物的脱甲基酶活性。施用肝单加氧酶诱导剂开蓬（具有雌激素活性）和灭蚁灵（无雌激素活性）也会增加雌二醇的2-羟基化。为作比较，还研究了经典雌激素（雌二醇和己烯雌酚）、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）对雌二醇-2-羟基化的影响。用雌二醇处理去卵巢和肾上腺切除（ovex/adx）的雌性大鼠或用己烯雌酚处理ovex/adx动物对雌二醇-2-羟基化没有影响。同样，他莫昔芬也不会改变雌二醇-2-羟基化的速率。用3-甲基胆蒽处理ovex/adx大鼠不会影响雌二醇-2-羟基化的速率。相比之下，用苯巴比妥处理的ovex/adx雌性大鼠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了2-羟基雌二醇；没有证据表明在雌二醇的其他位点形成了羟基化的主要代谢产物。目前的研究结果排除了先前观察到的用o,p'DDT或他莫昔芬预处理对雌二醇介导的ODC诱导作用的抑制（见上述引用文章）是由于肝单加氧酶对雌二醇的羟基化作用增强所致的可能性。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具有的雌激素（或抗雌激素）特性之间没有相关性。
