Induction of estradiol-2-hydroxylase and ethoxyresorufin-O-deethylase by 3-substituted indole compounds.
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.
Wong
D C
DC
Department of Biochemistry, The Chinese University of Hong Kong, Shatin.
Fong
W P
WP
Lee
S S
SS
Kong
Y C
YC
Cheng
K F
KF
Stone
G
G
D000470:Alkaloids / Q000494:pharmacology*; D000818:Animals; D003281:Contraceptives, Postcoital / Q000494:pharmacology*; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004790:Enzyme Induction; D004965:Estrogen Antagonists / Q000494:pharmacology; D005260:Female; D007211:Indoles / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D018336:Receptors, Aryl Hydrocarbon / Q000187:drug effects; D013250:Steroid Hydroxylases / Q000378:metabolism*
D000470:Alkaloids; D003281:Contraceptives, Postcoital; D004965:Estrogen Antagonists; D007211:Indoles; D018336:Receptors, Aryl Hydrocarbon; D003577:Cytochrome P-450 Enzyme System; C047409:yuehchukene; D013250:Steroid Hydroxylases; D019363:Cytochrome P-450 CYP1A1; C020120:estrogen 2-hydroxylase