Ng P C, Ho D D, Ng K H, Kong Y C, Cheng K F, Stone G
Biochemistry Department, Chinese University of Hong Kong, Shatin, New Territories.
Eur J Pharmacol. 1994 Oct 13;264(1):1-12. doi: 10.1016/0014-2999(94)90628-9.
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.
在大鼠子宫增重、小鼠阴道涂片及MCF-7细胞生长试验中观察到了月桂烯的抗雌激素作用。虽然月桂烯本身在这些生物测定模型中具有雌激素活性，但月桂烯与最佳剂量的3,17β-雌二醇（雌二醇）共同给药可减弱仅由雌二醇引起的最大雌激素反应。月桂烯对大鼠子宫肥大的抗雌激素作用通过这些组织中鸟氨酸脱羧酶活性的平行减弱得到了证实。月桂烯与大鼠、小鼠及MCF-7细胞雌激素受体结合，相对结合亲和力为1/150至1/300。这种结合亲和力与子宫增重试验和MCF-7细胞生长所确定的雌激素活性呈正相关。然而，这种雌激素作用与较弱激动剂的竞争性受体结合程度无关。吲哚-3-甲醇和甲基丁二烯基吲哚可在大鼠肝脏和MCF-7细胞中诱导乙氧基异吩恶唑酮O-脱乙基酶和雌二醇-2-羟化酶。据推测，月桂烯的“游离”吲哚部分可能具有类似的诱导活性。因此，月桂烯可能具有双重药理功能。虽然完整分子是一种弱雌激素，但月桂烯中的“游离”吲哚部分可能会诱导雌二醇-2-羟化酶的增强，从而终止内源性雌激素池的生物活性。在不直接使用他莫昔芬或芳香化酶抑制剂的情况下降低绝经后乳腺癌患者的雌激素水平有明显益处。月桂烯可能符合这一目的。在此背景下，目前正在认真研究一种羟基化月桂烯类似物的药理评价以及甲基丁二烯基吲哚酸缩合产物的抗雌激素作用。
