王 洋,陆远富,周少玉,石京山,刘 杰

    (遵义医学院 药理学教研室暨基础药理省部共建教育部重点实验室, 贵州 遵义 563099)

    基础医学研究

    亚急性汞暴露对小鼠肾汞含量及肾转运体表达的影响

    王洋,陆远富,周少玉,石京山,刘杰

    (遵义医学院 药理学教研室暨基础药理省部共建教育部重点实验室, 贵州 遵义563099)

    [摘要]目的 探讨亚急性汞暴露对小鼠肾汞含量及肾转运体表达的影响。方法 选取成年昆明种小鼠35只, 随机分成5组, 每组7只, 分别用蒸馏水、氯化汞(32 mg/kg)、甲基汞(2.6 mg/kg)、朱砂(300 mg/kg)和安宫牛黄丸(3 000 mg/kg)灌胃给药, 1天1次, 44 d后收集肾组织, 采用原子荧光分光光度计检测肾汞含量, 用RT-PCR法检测肾转运体mRNA的表达。结果 与空白组比较, 氯化汞组的肾汞蓄积含量是空白组的300倍, 甲基汞组是空白组的40倍, 而朱砂和安宫牛黄丸组没有明显变化。进一步研究发现: 氯化汞诱导有机阴离子转运体Oat1增加6倍, Oat3增加60倍, Oatp4c1增加8倍; 诱导外排转运体Mdr1b增加6倍, Mate2-k增加11倍; 抑制转运体Oat2降低95%, Oatp1a降低85%, 而Urat1增加10倍。甲基汞诱导转运体Oat3增加17倍, Mate2-k增加10倍, Urat1增加7倍, 抑制转运体Oat2降低50%, Mrp6降低60%。朱砂诱导Oat3增加20倍。结论 氯化汞、甲基汞、朱砂和安宫牛黄丸肾汞蓄积程度不同, 其主要原因是对肾转运体的影响不同。

    [关键词]氯化汞; 甲基汞; 硫化汞；朱砂; 安宫牛黄丸; 汞蓄积; 肾转运体

    Renal transporters mediate the renal secretion and reabsorption of exogenous and endogenous substances and are sensitive to toxic insults. Alterations in renal transporters can result in unexpected toxic effects and altered pharmacokinetics of drugs and other chemicals[1-5]. At least 37 transporters have been identified in mouse kidneys[6-7], and 29 transporters in brush-border and basolateral membrane of rat kidney have been quantified by proteomics recently. Renal transporters are categorized into four classes: (1)Basolateral uptake transporters such as organic anion transporterOat1 andOat3, organic cation transporterOct1,Oct2 and organic anion transporting polypeptideOatp4c1; (2)Apical brush-border membrane efflux transporters such as multidrug resistance-associated proteinMrp2,Mrp4, multidrug and toxin extrusionMate1,Mate2-k, breast cancer resistance proteinBcrp, and multidrug resistance proteinMdr1b; (3)Apical uptake transporters such as uric acid transporterUrat1andOatp1a1;(4) Basolateral transporter to efflux chemicals from tubule cells to blood such as the organic solute transporterOstαandOstβ[8].Transporters in the kidney play critical roles in detoxification of xenobiotics, and are sensitive to a wide variety of drugs and toxicants[1,9]. For example, Oats transport metals, drugs, and other toxicants into renal cells and result in higher concentration of toxicants in the kidney leading to nephrotoxicity[10-12]. Transporters, such asOcts,OctnsandMates, mediate the uptake, elimination and distribution of cationic drugs, toxicants, and environmental waste products[7,13]. TheMrpsplay a critical role in the tubular efflux of a wide variety of toxicants[14]. Kidney is the primary target organ that takes up and accumulates HgCl2and MeHg from the circulation[15]. It is known thatOat1 andOat3 mediate Hg uptake into kidneys[12,16], and deletion ofOat1 protects against HgCl2nephrotoxicity[17].Mrp2 plays a role in renal Hg elimination into the urine[3,18-19]. The acute effects of HgCl2and MeHg on renal transporters have been documente, however, little is known about mercury sulfide accumulation in the kidney and interaction with renal transporters, especially following repeated exposures. Mercury sulfide, either in the form of cinnabar (α-HgS) or metacinnabar (β-HgS), are included in some traditional medicines. The inclusion of heavy metals in herbal medicines may pose a potential risk to public health that has receiving growing attention worldwide. We have recently reported the differential nephrotoxicity of HgCl2, MeHg from HgS and HgS-containing traditional medicines following repeated exposures to mice[20], with marked differences in renal Hg accumulation. Thus, we hypothesize that HgS has less effects on renal transporters because of the low accumulation of Hg in kidneys. The present study was aimed to examine this hypothesis and to determine whether there is a correlation between the effects of repeated Hg exposure on renal transporters and their renal accumulation. ......