Regulation of Renal Xenobiotic Transport by Estrogens

描述（由申请人提供）：肾近端小管将底物从血液中分泌到尿液中，对于从体循环和体外清除潜在有害的外源性药物起着至关重要的作用。许多这样的外源药物是有机阴离子底物，因此可以通过与基底外侧膜有机阴离子运输（OAT）途径的相互作用被清除。最近，人们开始关注OAT通路的细胞调控，特别是OAT1-和oat3介导的转运。了解OAT1和OAT3的调控具有重要的现实意义，因为抑制或阻止有机阴离子运输的因素可能会增加对危险的外源性药物的暴露，从而产生或至少加剧毒性，而刺激有机阴离子分泌的因素可能会增加外源性药物的排泄，从而减少环境暴露。研究表明，各种激素系统的调节调节肾近端小管中各种运输过程的表达和生理功能。性类固醇激素睾酮和雌激素可能分别上调或下调肾脏有机阴离子运输，并可能解释异种生物积累、排泄和毒性反应的性别相关差异。在一些研究中，与雌激素相关的有机阴离子运输减少与毒性易感性增加有关。尽管在外源运输中表现出与性别相关的差异，但对性类固醇激素调节运输，特别是雌激素知之甚少。此外，各种内分泌干扰化学物质（EDCs）的存在，具有性类固醇激素和特别是雌激素活性的环境化学物质（即异种雌激素）可能通过其雌激素作用，下调参与肾脏积累和排泄的各种转运蛋白。为此，该提案将解决以下总体目标：1)表征内源性雌激素，17 -雌二醇和环境外源雌激素如己烯雌酚（DES）和染料木素对肾近端小管有机阴离子运输（OAT1和OAT3）的影响；2)确定这些雌激素介导其运输调节控制的机制。

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.