Regulation of Renal Xenobiotic Transport by Estrogens

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DESCRIPTION (provided by applicant): Secretion of substrates from the blood into the urine by the renal proximal tubule plays an essential role for removal of potentially hazardous xenobiotics from the systemic circulation and out of the body. Many such xenobiotics are organic anion substrates and may, therefore, be cleared via interaction with the basolateral membrane organic anion transport (OAT) pathway. Recently, attention has been given to the study of cellular regulation of the OAT pathways, particularly OAT1- and OAT3-mediated transport. Knowledge of the regulation of OAT1 and OAT3 has much practical significance since factors that either suppress or prevent organic anion transport may increase exposure to dangerous xenobiotics to produce or at least exacerbate toxicity, whereas factors that stimulate organic anion secretion may be employed to enhance xenobiotic excretion to reduce environmental exposure. Studies have demonstrated that regulation by various hormonal systems modulates the expression and physiological function of various transport processes in the proximal tubule of the kidney. The sex steroid hormones testosterone and estrogen may serve to upregulate or down regulate, respectively, renal organic anion transport and may account for sex-related differences in xenobiotic accumulation, excretion and response to toxicity. The decrease in organic anion transport associated with estrogen was reported in several studies to be related to an increased susceptibility to toxicity. In spite of the manifestation of gender-related differences in xenobiotic transport, little is understood about sex steroid hormone modulation of transport, particularly estrogens. Also, the presence of various endocrine disrupting chemicals (EDCs), environmental chemicals that possess sex steroid hormone and particularly estrogenic activity (i.e., xenoestrogens) may, through their estrogenic effects, down regulate various transporters involved in renal accumulation and excretion of xenobiotics. To this end the proposal will address the following overall objectives: 1) To characterize the effect of endogenous estrogen, 17beta-estradiol and the environmental xenoestrogens such as diethylstilbestrol (DES) and genistein on renal proximal tubule organic anion transport (OAT1 and OAT3) and 2) to determine the mechanisms by which these estrogens mediate their regulatory control of transport.