Division of Pathology and Laboratory Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, OH 45229, USA.
Carcinogenesis. 2010 May;31(5):886-93. doi: 10.1093/carcin/bgq025. Epub 2010 Jan 28.
We describe for the first time the chemopreventive effects of S-(-)equol and R-(+)equol, diastereoisomers with contrasting affinities for estrogen receptors (ERs). S-(-)equol, a ligand for ERbeta, is an intestinally derived metabolite formed by many humans and by rodents consuming diets containing soy isoflavones. Whether the well-documented chemopreventive effect of a soy diet could be explained by equol's action was unclear because neither diastereoisomers had been tested in animal models of chemoprevention. Sprague-Dawley rats (n = 40-41 per group) were fed a soy-free AIN-93G diet or an AIN-93G diet supplemented with 250 mg/kg of S-(-)equol or R-(+)equol beginning day 35. On day 50, mammary tumors were induced by dimethylbenz[a]anthracene and thereafter, animals were palpated for number and location of tumors. On day 190, animals were killed and mammary tumors were removed and verified by histology, and the degree of invasiveness and differentiation was determined. S-(-)equol and R-(+)equol plasma concentrations measured on days 35, 100 and 190 by tandem mass spectrometry confirmed diet compliance and no biotransformation of either diastereoisomer. In this model, S-(-)equol had no chemopreventive action, nor was it stimulatory. In contrast, R-(+)equol compared with Controls reduced palpable tumors (P = 0.002), resulted in 43% fewer tumors (P = 0.004), increased tumor latency (88.5 versus 66 days, P = 0.003), and tumors were less invasive but showed no difference in pattern grade or mitosis. Both enantiomers had no effect on absolute uterine weight but caused a significant reduction in body weight gain. In conclusion, the novel finding that the unnatural enantiomer, R-(+)equol, was potently chemopreventive warrants investigation of its potential for breast cancer prevention and treatment.
我们首次描述了 S-(-)雌马酚和 R-(+)雌马酚的化学预防作用，这两种非对映异构体对雌激素受体（ER）具有截然不同的亲和力。S-(-)雌马酚是一种 ERβ配体，是许多人和啮齿动物在食用含有大豆异黄酮的饮食后，由肠道衍生形成的代谢物。由于尚不清楚大豆饮食的良好化学预防作用是否可以通过雌马酚的作用来解释，因此这两种非对映异构体都没有在化学预防的动物模型中进行测试。40-41 只 Sprague-Dawley 大鼠（每组）在第 35 天开始分别喂食无大豆 AIN-93G 饮食或补充 250mg/kg S-(-)雌马酚或 R-(+)雌马酚的 AIN-93G 饮食。第 50 天，用二甲基苯并[a]蒽诱导乳腺肿瘤，此后通过触诊来确定肿瘤的数量和位置。第 190 天，处死动物，切除乳腺肿瘤并通过组织学验证，确定肿瘤的侵袭程度和分化程度。第 35、100 和 190 天通过串联质谱法测量 S-(-)雌马酚和 R-(+)雌马酚的血浆浓度，以证实饮食依从性且两种非对映异构体均未发生生物转化。在该模型中，S-(-)雌马酚没有化学预防作用，也没有刺激作用。相比之下，与对照组相比，R-(+)雌马酚减少了可触及的肿瘤（P=0.002），肿瘤数量减少了 43%（P=0.004），肿瘤潜伏期延长了 88.5 天（P=0.003），肿瘤侵袭性降低，但形态分级或有丝分裂无差异。两种对映体均对子宫重量无影响，但显著降低了体重增加。综上所述，具有新颖性的发现是，非天然对映体 R-(+)雌马酚具有强大的化学预防作用，这值得进一步研究其在乳腺癌预防和治疗方面的潜力。
