Regulation of Renal Xenobiotic Transport by Estrogens

描述(由申请人提供)：通过肾脏近端小管将底物从血液分泌到尿液中，对于将潜在危险的外来物质从体循环和体外清除起着至关重要的作用。许多这样的外源物质是有机阴离子底物，因此可以通过与基侧膜有机阴离子转运(OAT)途径的相互作用而被清除。最近，对燕麦转运蛋白途径的细胞调控，特别是OAT1和OAT3介导的转运的研究受到了重视。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转运的因素可能会增加危险的外源物质的暴露，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被用来增加外源物质的排泄，以减少环境暴露。研究表明，各种激素系统的调节调节了肾脏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有机阴离子转运，并可能解释与性别有关的异物积累、排泄和毒性反应的差异。据多项研究报道，雌激素导致的有机阴离子转运减少与其对毒性的敏感性增加有关。尽管在异种运输中表现出与性别相关的差异，但对性类固醇激素对运输的调节，特别是雌激素，知之甚少。此外，各种内分泌干扰物(EDCs)、具有性类固醇激素特别是雌激素活性的环境化学品(即异种雌激素)的存在，可能通过其雌激素效应下调参与外源物质在肾脏积累和排泄的各种转运体。为此，该提案将涉及以下总体目标：1)表征内源性雌激素、17β-雌二醇以及环境中的异种雌激素如己烯雌酚(DES)和金雀异黄素(Genistein)对肾近端小管有机阴离子转运(OAT1和OAT3)的影响；2)确定这些雌激素调节其转运的机制。

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.