Gender difference affects absorption and disposition of soy isoflavones in rats

Female Sprague-Dawley rats showed 2-fold higher total oral bioavailability (14C genistein) than male rats. Due to experimental limitations of measurement of radioactivity count, the absolute oral bioavailability of genistein and its phase II metabolites is still unknown. In this study, gender-dependent differences in oral bioavailability of genistein (20mg/kg) in male and female SD rats were determined. Female rats showed significantly higher (2 fold) oral bioavailability of total genistein in female than in male rats. The gender difference observed was due to significantly higher (4 fold) plasma genistein glucuronide concentrations in female than in male SD rats. These results were consistent with the gender-dependent differences in genistein absorption and disposition in rats using rat intestinal perfusion model. In perfusion model, female rats showed significantly higher biliary excretion of genistein glucuronide than in male rats, suggesting higher enterohepatic recycling in female rats as primary mechanism of action for higher oral genistein bioavailability in female than male rats. We also identified that hormonal changes as the result of estrus cycle play an important role in genistein absorption and disposition in female rats. We further compared the oral bioavailability of genistein in control female and female ovariectomized SD rats to determine if the difference in gender was due to differences in female sex hormones produced by ovaries. To our surprise, female ovariectomized rats showed higher (2.5 fold) oral bioavailability of total genistein than in control female rats, including higher plasma AUC of genistein (2 fold), genistein glucuronide (3 fold), and genistein sulfate (25 fold). Interestingly, exogenous dose of estrogen did not reverse any of bioavailability enhancement effects shown in female ovariectomized rats. The mechanisms responsible for the higher bioavailability of genistein in female ovariectomized rats remain unknown and require further investigation. In conclusion, genistein displayed substantial and significant gender-dependent differences in oral bioavailability of total genistein. Moreover, removal of sex hormones produced in ovary significantly impaired genistein metabolism in female rats, and the effect was not reversed by exogenous estrogen administration.Pharmacological and Pharmaceutical Sciences, Department o