Studies on the in vivo and in vitro estrogenic activities of methoxychlor and its metabolites. Role of hepatic mono-oxygenase in methoxychlor activation☆

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Abstract

The injection of rats with methoxychlor stimulated uterine ornithine decarboxylase (ODC) activity and caused an increase in uterine weight 7 hr after injection. The di-demethylated derivative of methoxychlor {[2,2-bis(p-hydroxyphenyl-1,1,1-trichloroethane] (HPTE)} markedly stimulated rat uterine ODC and enlarged uterine wet weight 6 hr after administration. Because we previously demonstrated that HPTE, but not methoxychlor, inhibited the binding of [3H]estradiol-17β ([3H]E2) to uterine cytosolic estrogen receptor in vitro, we considered the possibility that the estrogenic activity of methoxychlor in vivo was due to biotransformation of methoxychlor. The evolution of formaldehyde occurred when methoxychlor was incubated with rat hepatic microsomes in the presence of NADPH, indicating that methoxychlor was O- demethylated in vitro. The demethylation of methoxychlor was inhibited when methoxychlor was incubated with microsomes in the presence of hexobarbital or 2-diethylaminoethyl diphenyl-propylacetate hydrochloride (SKF-525A), suggesting the involvement of mono-oxygenase. Furthermore, the demethylated products were resolved by thin-layer chromatography (t.l.c.) into three chromatographically distinct components more polar than methoxychlor. One of the products appears to be the di-demethylated derivative of methoxychlor, since it was chromatographically identical to HPTE in three t.l.c. systems. Each of the three components inhibited [3H]E2 binding to rat uterine cytosol in vitro; however, the metabolite with an Rf equal to that of HPTE demonstrated equal potency to HPTE with respect to suppression of [3H]E2 binding to uterine cytosol. The possible involvement of mono-oxygenase in biotransformation in methoxychlor into estrogenic metabolites in vivo is discussed.

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    ☆

    Part of this work was presented at the meeting of the American Society for Pharmacology and Experimental Therapeutics, August 21–25, 1977, Ohio State University, Columbus, OH [Pharmacologist19 (2), abstr. 411].

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