10种肾毒性中药对小鼠肾脏有机阴离子转运体的影响

Effects of 10 Kinds of Nephrotoxic TCM on Kidney Organic Anion Transporter in Mice

目的:研究10种肾毒性中药对小鼠肾脏有机阴离子转运体(Oats)中3个主要亚型(Oat1、Oat2、Oat3)的影响。方法:1 840只SPF级NIH小鼠随机分为正常对照(等容纯水)组,丙磺舒(30 mg/kg)组,羧甲基纤维素钠(CMC-Na)组与白头翁、延胡索、草乌、川乌、独活、皂角刺、虎杖、甘遂、侧柏叶、木香水煎剂高、低剂量组,ig给药,bid,连续5 d。末次给药1 h后,尾iv给予对氨基马尿酸(PAH,30 mg/kg),测定小鼠肾脏匀浆中PAH药动学参数与在1、5、10、15、20 min时间点的肾组织中PAH的蓄积量。用DAS 2.0分析软件计算血中PAH的药动学参数。分组与给药同上,末次给药1 h后制作肾切片置于PAH-buffer中,测定肾切片PAH摄取量。结果:与正常对照组比较,延胡索高剂量组,草乌高、低剂量组,独活高剂量组,虎杖高、低剂量组,侧柏叶高剂量组t1/2β升高;10种中药高、低剂量组Vd均降低;除独活低剂量组、皂角刺低剂量组、甘遂低剂量组外,其余用药组的CL均降低、AUC0-20 min均升高,差异均具有统计学意义(P<0.01或P<0.05)。与正常对照组比较,白头翁高剂量组,延胡索高剂量组,草乌高剂量组,川乌高、低剂量组,独活高、低剂量组,皂角刺高、低剂量组,虎杖高、低剂量组,甘遂高、低剂量组,侧柏叶高、低剂量组,木香高、低剂量组小鼠肾组织PAH蓄积量增加,差异有统计学意义(P<0.01或P<0.05)。与正常对照组比较,延胡索高剂量组,草乌高、低剂量组,皂角高、低剂量组,甘遂高剂量组,侧柏叶高、低剂量组,木香高剂量组小鼠肾切片PAH摄取量减少,差异有统计学意义(P<0.01或P<0.05)。结论:10种肾毒性中药可能通过抑制有机阴离子转运体Oat1、Oat2、Oat3而导致肾损伤。

OBJECTIVE：To study the effects of 10 kinds of nephrotoxic TCM on three main subtypes（Oat1,Oat2 and Oat3）of kidney organic anion transporter（Oats）in mice.METHODS：A total of 1 840 SPF NIH mice were randomly divided into normal control group（isovolumic pure water）,probenecid group（30 kg/mg）,sodium carboxymethyl cellulose（CMC）group,Pulsatillae radix,Corydalis rhizoma,Aconiti kusnezoffii radix,Aconiti radix,Angelicae pubescentis radix,Gleditsiae spina,Polygonum cuspidatum,Kansui radix,Platycladi cacumen,Aucklandiae radix high and low dose groups.Mice were treated twice a day for 5 d,ig.After 1 h of the last dosing,they were iv given PAH in tail（30 mg/kg）.The PAH pharmacokinetic parameters of the kidney homogenate were determined and the PAH intake in kidney tissue at the time point of 1,5,10,15 and 20 min was detected.The PAH in blood was analyzed by DAS 2.0 software.The grouping and dosing were the same as before,after 1 h of the last dosing,kidney slices were made and put into PAH-buffer.The PAH intake of kidney slices was determined.RESULTS：Compared with normal control group,the t1/2 βin C.rhizoma high dose group,A.kusnezoffii high and low dose groups,A.pubescentis high dose group,P.cuspidatum high and low dose groups and P.cacumen group were increased;Vdwere all decreased in 10 kinds of TCM high and low dose groups;except for A.pubescentis low dose group,G.spian low dose group and K.radix low dose group,the CL was decreased and AUC0-20 minwas increased in all other groups,with significant difference（P0.01 or P0.05）.Compared with normal control group,the content of PAH in kidney tissue in P.radix high dose group,C.rhizoma high dose group,A.kusnezoffii high dose group,A.radix high and low dose groups,A.pubescentis high and low dose groups,G.spina high and low dose groups,P.cuspidatum high and low dose groups,K.radix high and low dose groups,P.cacumen high and low dose groups and A.radix high and low dose groups were increased,with significant difference（P0.01 or P0.05）.Compared with normal control group,the intake of PAH in kidney slices in C.rhizoma high dose group,A.kusnezoffii high and low dose groups,G.spi-na high and low dose groups,K.radix high dose group,P.cacumen high and low dose groups and A.radix high dose group were decreased,with significant difference（P0.01 or P0.05）.CONCLUSIONS：The 10 kinds of nephrotoxic TCM probably induced kidney injury through inhibiting the Oat1,Oat2 and Oat3 of Oats.