Mixed estrogenic and anti-estrogenic activities of yuehchukene--a bis-indole alkaloid.
Anti-estrogenic effects of yuehchukene were observed in rat uterotrophic, mice vaginal smear and MCF-7 cell growth assays. Whereas yuehchukene per se was estrogenic in these bioassay models, the co-administration of yuehchukene and an optimal dose of 3,17 beta-estradiol (estradiol) could attenuate the maximum estrogenic response due to estradiol alone. The anti-estrogenic effect of yuehchukene in rat uterine hypertrophy was corroborated by a parallel attenuation of ornithine decarboxylase activity in these tissues. Yuehchukene binds to rat, mice and MCF-7 cell estrogen receptors with a relative binding affinity of 1/150 to 1/300. This binding affinity was positively related to estrogenicity as determined by uterotrophic assay and MCF-7 cell growth. However, this estrogenic effect did not correlate with the degree of competitive receptor binding by a weaker agonist. Indole-3-carbinol and methylbutadienylindole could induce ethoxyresorufin O-deethylase and estradiol-2-hydroxylase in rat liver and MCF-7 cells. It is postulated that the 'free' indole moiety of yuehchukene could possess similar induction activity. Thus yuehchukene may have a dual pharmacological function. While the intact molecule is a weak estrogen, the 'free' indole moiety in yuehchukene may induce an enhancement of estradiol-2-hydroxylase, thus terminating the biological activity of the endogenous estrogen pool. There is obvious benefit in attenuating the estrogen level in post-menopausal breast cancer patients without going directly to the use of tamoxifen or aromatase inhibitor. Yuehchukene may serve this purpose. In this context, the pharmacological evaluation of a hydroxylated yuehchukene analogue and the anti-estrogenic effect of methylbutadienylindole acid-condensation products are now being studied in earnest.
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Biochemistry Department, Chinese University of Hong Kong, Shatin, New Territories.
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Kong
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Cheng
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Stone
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D000470:Alkaloids / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D001667:Binding, Competitive; D001943:Breast Neoplasms / Q000188:drug therapy / Q000473:pathology; D002455:Cell Division; D003281:Contraceptives, Postcoital / Q000378:metabolism / Q000494:pharmacology*; D004958:Estradiol / Q000494:pharmacology; D004965:Estrogen Antagonists / Q000494:pharmacology*; D004967:Estrogens / Q000378:metabolism*; D005260:Female; D006801:Humans; D006984:Hypertrophy; D007211:Indoles; D051379:Mice; D009955:Ornithine Decarboxylase / Q000378:metabolism; D010052:Ovariectomy; D051381:Rats; D017207:Rats, Sprague-Dawley; D011960:Receptors, Estrogen / Q000378:metabolism; D013250:Steroid Hydroxylases / Q000378:metabolism; D014407:Tumor Cells, Cultured; D014599:Uterus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D014621:Vagina / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D014626:Vaginal Smears
D000470:Alkaloids; D003281:Contraceptives, Postcoital; D004965:Estrogen Antagonists; D004967:Estrogens; D007211:Indoles; D011960:Receptors, Estrogen; D004958:Estradiol; C030374:indole; C047409:yuehchukene; D013250:Steroid Hydroxylases; D009955:Ornithine Decarboxylase