Gender difference in the Oatp1-mediated tubular reabsorption of estradiol 17β-d-glucuronide in rats

Abstract

The gender difference in the urinary excretion of estradiol-17β-glucuronide (E2-17βG) was examined in rats. The urinary clearance of E2-17βG was >250 times lower in male than in female rats. No such major gender difference was observed in its biliary excretion or metabolism in kidney homogenate. Both plasma protein binding and inulin clearance were comparable in male and female rats, suggesting that this gender difference cannot be explained by glomerular filtration. The urinary clearance with respect to the plasma unbound E2-17βG in male rats was <1% of the glomerular filtration rate, indicating its potential reabsorption by the kidney, and this increased to a level comparable with that found in female rats when dibromosulfophthalein was coinfused. A marked increase in E2-17βG urinary excretion was also observed in male rats that had undergone orchidectomy. Testosterone injections given to female rats reduced the urinary excretion to a level comparable with that of control male rats. The concomitant change in the expression of the gene product for organic anion-transporting polypeptide Oatp1, of which E2-17βG is a typical substrate, was found in the kidney membrane fractions after these treatments. These results suggest that urinary E2-17βG excretion is subject to hormonal regulation and that the large gender difference can be explained by regulation in Oatp1-mediated reabsorption.