3 years ago

Identification of natural products as inhibitors of human organic anion transporters (OAT1 and OAT3) and their protective effect on mercury-induced toxicity.

Curtis D Klaassen, Gentao Li, Lifeng Han, Youcai Zhang, Wei Peng, Xiumei Gao, Xue Wang, Guanwei Fan
Mercury accumulates in kidneys and produces acute kidney injury. Semen cassiae (SC), a widely consumed tea and herbal medicine in Eastern Asia, has been reported to have protective effects on kidneys. In this study, SC extract was shown to almost abolish the histological alterations induced by mercuric chloride (HgCl2) in rat kidneys. A total of 22 compounds were isolated from SC, and 1,7,8-methoxyl-2-hydroxyl-3-methyl-anthraquinone was detected in SC for the first time. Among the 8 compounds identified in the blood of rats after SC treatment, 6 were strong inhibitors of human organic anion transporter 1 and 3 (OAT1 and OAT3). Inhibitory studies revealed that OAT1 and OAT3 were inhibited by SC constituents, in both a competitive and non-competitive manner. Both OAT1- and OAT3-overexpressing cells were susceptible to the cytotoxicity of the cysteine-mercury conjugate (Cys-Hg), but only OAT1-overexpressing cells could be protected by 200 μM probenecid or 10 μM of the 8 inhibitors in SC, suggesting that OAT1 is the major determinant in the cellular uptake of mercury. To facilitate the identification of inhibitors of OAT1 and OAT3, models of OAT1 and OAT3 were constructed using recently determined protein templates. By combining in silico and in vitro methods, inhibitors of OAT1 and OAT3 were predicted and validated from SC constituents. Collectively, the present study suggests that additional inhibitors of OAT1 and OAT3 can be predicted and validated from natural products by combining docking and in vitro screening, and could be a source of pharmaceutical compounds for developing treatments for mercury-induced kidney injury.

Publisher URL: http://doi.org/10.1093/toxsci/kfx216

DOI: 10.1093/toxsci/kfx216

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