Soy isoflavone phase II metabolism differs between rodents and humans: implications for the effect on breast cancer risk.

BACKGROUND: Human and animal studies have produced conflicting results with regard to the effect of soy isoflavones on breast cancer risk. This may be due to differences in isoflavone metabolism. OBJECTIVE: The objective of this study was to determine whether soy isoflavone phase II metabolism differs between humans and rodents. DESIGN: Circulating total and unconjugated isoflavone concentrations were determined by mass spectrometry in plasma samples from 7 separate studies: 1) in Sprague-Dawley rats and in 3 strains of mice fed commercial soy-containing diets; 2) in Sprague-Dawley rats gavaged with genistein; 3) in healthy adults who consumed single servings of soy nuts, soy milk, and tempeh; 4) in healthy adults subchronically given soy milk; 5) in healthy women orally administered 50 mg genistein; 6) in healthy women orally administered 20 mg pure S-(-)equol; and 7) in 6-mo-old infants fed soy infant formula and later, at age 3 y, a soy germ isoflavone supplement. RESULTS: The proportion of unconjugated genistein in plasma from adults and infants who consumed different soy foods, pure genistein, or an isoflavone supplement was <1% in steady state and <2% at peak concentrations. By contrast, rodents fed soy-containing diets conjugate isoflavones less efficiently. The plasma percentages of unconjugated genistein concentrations in Sprague-Dawley rats and C57BL/6, nude, and transgenic AngptL4B6 mice were 4.0 ± 0.6%, 4.6 ± 0.6%, 11.6 ± 0%, and 30.1 ± 4.3%, respectively, which represent 20, 23, 58, and 150 times that in humans. CONCLUSION: The markedly higher circulating concentrations of biologically active (unconjugated) genistein in certain strains of mice cast doubt on the value of the use of these rodents for gaining insight into the effects of isoflavones in humans, especially with regard to the effects on breast tissue.

Impact of perinatal exposure to equol enantiomers on reproductive development in rodents.

There is now considerable interest in the intestinally derived soy isoflavone metabolite, equol, which occurs in the enantiomeric forms, S-(-)equol and R-(+)equol, both differing in biological actions. Little is known about effects of either enantiomer on reproductive development, yet such knowledge is fundamental because of the recent commercialization of S-(-)equol as a dietary supplement. S-(-)equol and R-(+)equol were therefore investigated to determine their effects on reproductive development and fertility in the Sprague-Dawley rat. Neither enantiomer affected fertility, number of litters produced, number of pups per litter, number of male and female pups born, birth weight, anogenital distance, testicular descent or vaginal opening. Histological analysis showed no major abnormalities in ovary, testis, prostate or seminal vesicle tissue with dietary exposure to S-(-)equol or R-(+)equol, but both enantiomers triggered hyperplasia of uterine tissue. With R-(+)equol this stimulatory effect subsided after exposure was discontinued, but the effect of S-(-)equol was prolonged.

The chemopreventive action of equol enantiomers in a chemically induced animal model of breast cancer.

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.