大黄肾脏毒性部分机制研究  

Mechanism of nephrotoxicity of rhubarb in rats

作　　者：邓诺 易艳[1] 梁爱华[1] 李春英[1] 赵雍[1] 潘辰[1] 张宇实[1] 王连嵋[1] 韩佳寅[1] 刘素彦[1] 田婧卓 李桂琴[1] 刘靖 DENG Nuo;YI Yan;LIANG Ai-hua;LI Chun-ying;ZHAO Yong;PAN Chen;ZHANG Yu-shi;WANG Lian-mei;HAN Jia-yin;LIU Su-yan;TIAN Jing-zhuo;LI Gui-qin;LIU Jing(Key Laboratory of Beijingfor Identification and Safety Evaluation of Chinese Medicine.,Institute of Chinese Materia Medica,China Academy of Chinese Medical Sciences,Beijing 100700,China;School of Traditional Chinese Medicine,Capital Medical University,Beijing 100069,China)

机构地区：[1]中国中医科学院中药研究所中药鉴定与安全性检测评估北京市重点实验室,北京100700 [2]首都医科大学中医药学院,北京100069

出　　处：《中国中药杂志》2018年第13期2777-2783,共7页China Journal of Chinese Materia Medica

基　　金：国家“重大新药创制”科技重大专项(2015ZX09501004);国家公益性行业科研专项(201507004);中国中医科学院重点领域研究专项(ZZ10025);北京市科技计划项目(Z151100000115012,Z161100004916025)

摘　　要：该研究旨在探讨大黄剂量相关的肾脏毒性及其毒性机制。将SD大鼠随机分为正常组和大黄提取物高、低剂量组（16,2 g·kg-1,按照动物与人体表面积折算分别相当于临床剂量10,1.25倍）,连续灌胃给药1个月后,分析血液尿素氮（BUN）,肌酐（CRE）以及尿KIM-1,NGAL,进行肾脏组织形态学观察,检测肾脏OAT1,OAT3,clusterin等mRNA表达。结果显示,大黄低剂量组未见明显肾脏毒性。高剂量组可见轻中度肾脏病理损伤,其中雄性动物较重,伴有肾脏组织clusterin mRNA表达下调。高剂量组的常规肾脏功能指标血液BUN和CRE无明显变化,但尿液NGAL水平均较正常组提高51.53%,其中雄性动物增高更明显（与正常组比较P〈0.05）。低剂量组肾脏组织的OAT1,OAT3 mRNA表达较正常组有较大幅度增高,而高剂量组增高幅度较小。结果提示,大黄的肾脏毒性与剂量有关,临床用药时应合理控制剂量。肾脏组织中与阴离子物质转运有关的基因OAT1,OAT3 mRNA在大黄造成肾脏损伤过程中起到一定的代偿性保护作用,但在高剂量水平其代偿作用较弱。此外常规肾功能检测指标BUN,CRE对于大黄肾脏毒性的检出能力有限,建议增加尿液NGAL检测,有助于其肾毒性的监测。The aim of this study was to investigate the renal toxicity of rhubarb and its mechanism. The SD rats were randomly divided into three groups： normal group and two rhubarb extract groups（16,2 g·kg-1）. According to the dose conversion method between human and animal,rhubarb 16 g·kg-1 and 2 g·kg-1 were equivalent to 10 times and 1. 25 times of human clinical dose respectively. Rhubarb extract was administered by a gastric gavage to rats once daily for 30 days. Serum urea nitrogen（BUN）,creatinine（CRE） and urine KIM-1,NGAL and renal morphology were analyzed. The expressions of OAT1,OAT3 and clusterin mRNA in kidney were measured. The results showed that the low dose of rhubarb had no obvious renal toxicity. The high dose group showed mild and moderate renal injury and a down-regulation of clusterin mRNA expression in the kidney tissue. The renal toxicity in male animals was heavier than that in female animals. There was no significant change in blood BUN and CRE in the high dose group. But urine NGAL level of the high dose group increased by 51. 53% compared with normal group,of which male animals increased more significantly（P 0. 05,compared with the normal group）. The expressions of renal OAT1 and OAT3 mRNA in the low dose group were obviously higher than that in the normal group. The results indicated that the high dose of rhubarb could cause the renal toxicity. The dosage should be controlled reasonably in the clinical use. OAT1 and OAT3 mRNA related to anionic transport in kidney tissue played a compensatory protective role in rhubarb-induced renal injury. But the compensatory effect is relatively weak at the high dose level. In addition,routine renal function indicators BUN and CRE had limitation for monitoring the kidney toxicity of rhubarb. It is suggested that urine NGAL detection might be helpful for monitoring the renal toxicity of rhubarb.

关 键 词：大黄提取物 肾毒性 肾脏损伤因子 中性粒细胞明胶酶相关脂质运载蛋白 阴离子转运蛋白 

分 类 号：R285.5[医药卫生—中药学]