肉桂等八种中药对小鼠肾脏三种主要有机阴离子转运体的影响  

Effects of eight kinds of nephrotoxic Chinese drugs on three major organic anion transporters,Oat1,Oat2 and Oat3 in vivo in mice

作　　者：孙晨[1] 奇锦峰[1] 余文浩[1] 王永辉 林梅[3] 张娜[1] 

机构地区：[1]广州中医药大学中药学院药理教研室 [2]河南省驻马店市人民医院药剂科 [3]广东佛山南海中医院西药房

出　　处：《中国临床药理学与治疗学》2015年第9期985-992,共8页Chinese Journal of Clinical Pharmacology and Therapeutics

摘　　要：目的:检测8种具有肾毒性的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:肉桂等8种中药水煎剂(以高、低两个剂量)及纯水、丙磺舒(阳性对照)及羧甲基纤维素钠(CMC,丙磺舒溶媒)分别灌胃给NIH小鼠(每组雌雄各半),2次/d,连续5 d。最后一次给予供试品后1 h所有受试鼠逐一经尾静脉注入对氨基马尿酸(para-aminohippuric acid,PAH,30 mg/kg),然后在1、2.5、5、7.5、10、15和20 min时从各组分别取10只鼠安乐处死收集全血并迅速摘取双肾。匀浆各左肾(以Folin-酚法定量蛋白浓度)后以文献法定量其中及血清中的PAH浓度,以药动学软件(DAS2.0)分析血中PAH的主要药动学参数:消除半衰期(t1/2β)、分布容积(Vd)、总清除率(CL)及药时曲线下面积(AUC0-20 min);比较全部采血点中5个时间点(1、5、10、15、20 min)各组肾组织中的PAH蓄积量;从1 min采血点时的各组右肾提取总mRNA,以实时荧光定量PCR法比较各组小鼠肾脏中Oat1、Oat2、Oat3 mRNA的表达量。结果:与纯水组相比,益母草高剂量组,蜈蚣高、低剂量组的t1/2β显著延长(P<0.05,P<0.01),其余各组无明显改变(P>0.05)。除细辛低剂量组和益母草低剂量组外所有其他供试物组的Vd、CL和AUC0-20 min均发生显著变化:Vd变小(P<0.01),CL变慢(P<0.01),AUC0-20 min增大(P<0.01)。与纯水对照组相比,肾组织中的PAH蓄积量除冬虫夏草低剂量组、蜈蚣低剂量组外其余各组均显著升高(P<0.05,P<0.01)。与CMC组相比,丙磺舒组的mRNA表达量在Oat1、Oat3被显著上调(P<0.05,P<0.01),而在Oat2被显著下调(P<0.05);与纯水组相比,Oat1的mRNA表达水平在细辛、冬虫夏草、益母草、番泻叶、厚朴等各组被显著上调(P<0.05,P<0.01),而在蜈蚣组则被显著下调(P<0.05);肉桂、冬虫夏草、益母草、番泻叶、厚朴等各组的Oat2的mRNA表达量被显著上调(P<0.01);肉桂、厚朴两组的Oat3的mRNA表达水平被显著上调(P<AIM： To investigate the effects of eight kinds of nephrotoxic Chinese drugs on three major types of organic anion transporters, Oat1,Oat2 and Oat3 in vivo in mice. METHODS： Water decoction of eight kinds of nephrotoxic Chinese drugs was orally administered to NIH mice（ 50% of each gender per group） respectively at high and low dosages two times a day for 5 consecutive days. Also,there were groups of pure water control,Probenecid（ positive control） and Carboxymethylcellulose sodium（ CMC,vehicle for Probenecid）. One hour after the last dose at the 5th day,all the mice were intravenously given para-aminohippuric acid（ PAH） at a dose of 30 mg / kg. Mice（ n = 10 / group） were euthanized and whole blood were collected at 1,2. 5,5,7. 5,10,15,20 min respectively. Kidneys were isolated immediately after bleeding. Left kidney was homogenized for PAH accumulation test（ protein concentrations were quantified by Folin-phenol method）. The concentrations of PAH in sera and in kidney homogenates were determined by the literature method. Major pharmacokinetic parameters（ t1 /2β,CL,Vd,AUC0- 20 min） of PAH in blood were calculated by pharmacokinetic software（ DAS 2. 0）. Total mRNA was extracted from right kidneys isolated from first bleeding（ 1 min after PAH injection） and the mRNA expressions for Oat1,Oat2 and Oat3 were quantified by real-time PCR. RESULTS： Compared with water control group,t1 /2βof high dosage of Herba Leonuri,both high and low dosage of Scolopendra were significantly prolonged（ P〈 0. 05,0. 01）.With the exception of low dosage of Radix et Rhizoma Asari and Herba Leonuri,Vd,CL and AUC0-20 min in all other groups were considerably changed,Vd decreased（ P〈 0. 01）,CL reduced（ P〈 0. 01）and AUC0-20 minincreased（ P〈 0. 01）. PAH accumulation in kidneys was extensively increased（ P〈 0. 05,P〈 0. 01） in all other groups except from low dosage of Cordyceps and Scolopendra. Compared with CMC group,the mRNA expressions of Oat1 and Oat3 were significant

关 键 词：肾毒性 中药 有机阴离子转运体 对氨基马尿酸清除试验 MRNA表达 

分 类 号：R965.2[医药卫生—药理学]