Induction of estradiol-2-hydroxylase and ethoxyresorufin-O-deethylase by 3-substituted indole compounds

Estrogen can be hydroxylated at both 2- and 16 alpha-positions. These two r eactions are mutually exclusive. The 2-hydroxylated estrogen is relatively inactive compared with the 16 alpha-derivative; hence, one approach in anti -estrogenic therapy is to look for drugs that can induce the 2-hydroxylatio n 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 c ompounds examined included 2'- and 3'-methylbutadienyl-indoles and their re spective acid condensation products, isopropyl indolocarbazole and yuehchuk ene; positional isomers of indole carbinols and carboxyaldehydes, as well a s 3-methylcholanthrene, the prototype inducer of cytochrome P450 1A1.Our re sults demonstrated that while all of them were capable of inducing cytochro me P450 1A1-mediated ethoxyresorufin-O-deethylase activity, only the 3' iso mers could induce estradiol-2-hydroxylase activity. The induction of these two activities did not show any direct correlation, suggesting that cytochr ome P450 1A1 was not the same enzyme catalyzing both ethoxyresorufin-O-deet hylation and estradiol-2-hydroxylation. Nevertheless, both inductions were mediated by the aryl hydrocarbon receptor. Among the compounds tested, yueh chukene showed competitive binding to estrogen receptor. This, together wit h the induction of estradiol-2-hydroxylase activity, may account for the an ti-estrogenic effect of yuehchukene. (C) 1998 Elsevier Science B.V. All rig hts reserved.