MIXED ESTROGENIC AND ANTIESTROGENIC ACTIVITIES OF YUEHCHUKENE - A BIS-INDOLE ALKALOID

Anti-estrogenic effects of yuehchukene were observed in rat uterotroph ic, mice vaginal smear and MCF-7 cell growth assays. Whereas yuehchuke ne per se was estrogenic in these bioassay models, the co-administrati on of yuehchukene and an optimal dose of 3,17 beta-estradiol (estradio l) could attenuate the maximum estrogenic response due to estradiol al one. The anti-estrogenic effect of yuehchukene in rat uterine hypertro phy was corroborated by a parallel attenuation of ornithine decarboxyl ase activity in these tissues. Yuehchukene binds to rat, mice and MCF- 7 cell estrogen receptors with a relative binding affinity; of 1/150 t o 1/300. This binding affinity was positively related to estrogenicity as determined by uterotrophic assay and MCF-7 cell growth. However, t his estrogenic effect did not correlate with the degree of competitive receptor binding by a weaker agonist. Indole-3-carbinol and methylbut adienylindole could induce ethoxyresorufin O-deethylase and estradiol- 2-hydroxylase in rat live; and MCF-7 cells. It is postulated that the 'free' indole,moiety of yuehchukene could possess similar induction ac tivity. Thus yuehchukene may have a dual pharmacological function. Whi le the intact molecule is a weak estrogen, the 'free' indole moiety in yuehchukene may induce an enhancement of estradiol-2-hydroxylase, thu s terminating the biological activity of the endogenous estrogen pool. There is obvious benefit in attenuating the estrogen level in post-me nopausal breast cancer patients without going directly to the use of t amoxifen or aromatase inhibitor. Yuehchukene may serve this purpose. I n this context, the pharmacological evaluation of a hydroxylated yuehc hukene analogue and the anti-estrogenic effect of methylbutadienylindo le acid-condensation products are now being studied in earnest.