contraceptives--postcoital and yuehchukene

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.

Topics: Alkaloids; Animals; Contraceptives, Postcoital; Cytochrome P-450 CYP1A1; Cytochrome P-450 Enzyme System; Enzyme Induction; Estrogen Antagonists; Female; Indoles; Mice; Mice, Inbred BALB C; Receptors, Aryl Hydrocarbon; Steroid Hydroxylases

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.

Topics: Alkaloids; Animals; Binding, Competitive; Breast Neoplasms; Cell Division; Contraceptives, Postcoital; Estradiol; Estrogen Antagonists; Estrogens; Female; Humans; Hypertrophy; Indoles; Mice; Ornithine Decarboxylase; Ovariectomy; Rats; Rats, Sprague-Dawley; Receptors, Estrogen; Steroid Hydroxylases; Tumor Cells, Cultured; Uterus; Vagina; Vaginal Smears

(+/-)-Yuehchukene is a dimeric indole alkaloid with potent anti-implantation activity in rats. Since (+/-)-yuehchukene occurs in nature as a racemate, it would be desirable to find out which enantiometer is the bio-active form. To this end, S(-)-camphor-yuehchukene and R(+)-camphor-yuehchukene were synthesised and tested in three bioassay models. It was found that the R(+) enantiomer was the active form. It was equipotent with (+/-)-yuehchukene in both anti-implantation and estrogenic activity tests. It seems fair to conclude that both activities reside in the same molecule.

Topics: Alkaloids; Animals; Camphor; Chromatography, High Pressure Liquid; Contraceptives, Postcoital; Dose-Response Relationship, Drug; Drug Combinations; Embryo Implantation; Ethinyl Estradiol; Female; Rats; Rats, Inbred Strains; Stereoisomerism; Structure-Activity Relationship

Topics: Alkaloids; Chemical Phenomena; Chemistry; Contraceptives, Postcoital