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

Eur J Pharmacol. 1998 Nov 27;362(1):87-93. doi: 10.1016/s0014-2999(98)00742-0.

Abstract

Estrogen can be hydroxylated at both 2- and 16alpha-positions. These two reactions are mutually exclusive. The 2-hydroxylated estrogen is relatively inactive compared with the 16alpha-derivative; hence, one approach in anti-estrogenic therapy is to look for drugs that can induce the 2-hydroxylation 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 compounds examined included 2'- and 3'-methylbutadienyl-indoles and their respective acid condensation products, isopropyl indolocarbazole and yuehchukene; positional isomers of indole carbinols and carboxyaldehydes, as well as 3-methylcholanthrene, the prototype inducer of cytochrome P450 1A1. Our results demonstrated that while all of them were capable of inducing cytochrome P450 1A1-mediated ethoxyresorufin-O-deethylase activity, only the 3' isomers could induce estradiol-2-hydroxylase activity. The induction of these two activities did not show any direct correlation, suggesting that cytochrome P450 1A1 was not the same enzyme catalyzing both ethoxyresorufin-O-deethylation and estradiol-2-hydroxylation. Nevertheless, both inductions were mediated by the aryl hydrocarbon receptor. Among the compounds tested, yuehchukene showed competitive binding to estrogen receptor. This, together with the induction of estradiol-2-hydroxylase activity, may account for the anti-estrogenic effect of yuehchukene.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alkaloids / pharmacology*
  • Animals
  • Contraceptives, Postcoital / pharmacology*
  • Cytochrome P-450 CYP1A1 / metabolism*
  • Cytochrome P-450 Enzyme System / metabolism*
  • Enzyme Induction
  • Estrogen Antagonists / pharmacology
  • Female
  • Indoles / pharmacology*
  • Mice
  • Mice, Inbred BALB C
  • Receptors, Aryl Hydrocarbon / drug effects
  • Steroid Hydroxylases / metabolism*

Substances

  • Alkaloids
  • Contraceptives, Postcoital
  • Estrogen Antagonists
  • Indoles
  • Receptors, Aryl Hydrocarbon
  • Cytochrome P-450 Enzyme System
  • yuehchukene
  • Steroid Hydroxylases
  • Cytochrome P-450 CYP1A1
  • estrogen 2-hydroxylase