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Bulger WH, Kupfer D: Effect of xenobiotic estrogens and structurally related compounds on 2-hydroxylation of estradiol and on other monooxygenase activities in rat liver. Biochem Pharmacol. 1983 Mar 15;32(6):1005-10.
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. |
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