Human sulphotransferases are involved in the activation of aristolochic acids and are expressed in renal target tissue
Human sulphotransferases are involved in the activation of aristolochic acids and are expressed in renal target tissue
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DOI：
10.1002/ijc.21480
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发表时间：
2006-03-01
影响因子：
6.4
通讯作者：
Glatt, H
中科院分区：
文献类型：
--
作者：
Meinl, W;Pabel, U;Glatt, H
使用含有马兜铃属的草药制剂会导致人类进行性肾病和尿路上皮癌。对人类靶组织中形成的 DNA 加合物的分析和动物模型研究指出了植物次生代谢物马兜铃酸在这些效应中的主要作用。只有少数含有马兜铃的产品使用者出现肾病和癌症，这表明个体易感性存在差异。代谢激活和失活的差异经常影响对化学品的敏感性。其他研究表明，马兜铃酸活化为 DNA 反应性和诱变代谢物需要还原其芳基硝基。许多硝基芳烃和氨基芳烃经过适当的 I 相代谢后，在乙酰基转移酶或磺基转移酶 (SULT) 的存在下，其生物活性会大大增强。在本研究中，我们证明人类 SULT 在细菌和哺乳动物靶细胞中的表达增强了马兜铃酸的诱变活性。使用鼠伤寒沙门氏菌 TA1538 作为受体生物体，我们鉴定了所有 12 种人类 SULT 形式的表达。 SULT1A1 导致马兜铃酸的致突变性增强最强烈。 SULT1B1 也观察到了一些激活，但其余形式则没有。与对照细胞相比，使用鼠伤寒沙门氏菌 TA100 和中国仓鼠 V79 衍生的靶细胞证实了 SULT1A1 在马兜铃酸激活中的作用，这些靶细胞被设计用于表达人 SULT1A1。此外，SULT1A1 抑制剂五氯苯酚可强烈降低马兜铃酸对 V79-hCYP2E1-hSULT1A1 细胞的诱变作用。此外，我们通过免疫印迹分析证明 SULT1A1 和 SULT1B1 在人肾中表达，但其水平显着低于肝脏中的水平。最后，我们讨论了其他组织中产生的反应性硫酸结合物转移到肾脏和输尿管的可能性。 (c) 2005 年 Wiley-Liss, Inc.
Use of herbal preparations containing Aristolochia species has led to progressive nephropathy and urothelial cancer in humans. Analysis of DNA adducts formed in human target tissues and studies in animal models have pointed out a major role of the secondary plant metabolites, aristolochic acids, in these effects. Only a minority of the users of Aristolochia-containing products developed nephropathy and cancer, suggesting differences in individual susceptibility. Differences in metabolic activation and inactivation frequently affect the susceptibility towards chemicals. Others have shown that the activation of aristolochic acids to DNA-reactive and mutagenic metabolites requires reduction of their aryl nitro group. The biological activity of numerous nitro- and aminoarenes, after appropriate phase I metabolism, is strongly enhanced in the presence of acetyl-transferases or sulphotransferases (SULTs). In the present study, we demonstrate that expression of human SULTs in bacterial and mammalian target cells reinforces the mutagenic activity of aristolochic acids. Using Salmonella typhimurium TA1538 as the recipient organism, we identified the expression of all 12 human SULT forms. SULT1A1 led to the strongest increase in the mutagenicity of aristolochic acids. Some activation was also observed with SULT1B1, but not with the remaining forms. The role of SULT1A1 in the activation of aristolochic acids was corroborated using S. typhimurium TA100- and Chinese hamster V79-derived target cells engineered for expression of human SULT1A1 when compared with control cells. Furthermore, pentachlorophenol, an inhibitor of SULT1A1, strongly reduced the mutagenic effect of aristolochic acids in V79-hCYP2E1-hSULT1A1 cells. Moreover, we demonstrate that SULT1A1 and SULT1B1 are expressed in human kidney using immunoblot analysis, but their levels are substantially lower than in liver. Finally, we discuss the possibility that reactive sulphuric acid conjugates produced in other tissues are transferred to kidney and ureter. (c) 2005 Wiley-Liss, Inc.