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. Am J Clin Nutr 2011;94:1284-94.