关木通提取物诱导的大鼠慢性肾毒性变化及 与血药浓度的关系

目的 :观察长期应用不同剂量关木通提取物诱导的大鼠肾毒性的变化,并分析其与马兜铃酸A血药浓度的关系。 方法 :SD大鼠随机分为5组:正常对照组,低盐对照组,低、中、高剂量组,于给药后第4和6周观察大鼠肾功能和肾组织形态学的变化。马兜铃酸A血药浓度采用液质联用(LC/MS/MS)法测定。 结果 :与低盐对照组相比,药后第2周低、中、高剂量组尿量增多,第4周时尿量减少,低、中剂量组其他各指标无明显变化,高剂量组尿蛋白和尿素氮(BUN)升高;药后第6周时,高剂量组尿量进一步减少,尿蛋白、肌酐(Crea)和BUN明显升高;病理表现为肾小管细胞空泡变性及小动脉和肾间质病变;高剂量组各种变化较低、中剂量组更为明显。各项检测指标在2个对照组间差异无统计学意义。药后6周血浆中马兜铃酸A浓度极低。 结论 :大鼠长期应用关木通提取物可导致肾脏功能和组织学病变,且病变程度与用药时间和剂量有明显的相关性,而与马兜铃酸A血药浓度可能无关。

Changes of Caulis Aristolochiae Manshuriensis Extract-induced Chronic Nephrotoxicity and Relationship between Changes and Plasma Concentration

Objective: To observe the renal changes of aristolochic acid-induced nephrotoxicity by long-term using different dose of Caulis Aristolochiae Manshuriensis Extract (CAME) in rats, and investigate the relationship between the changes and blood aristolochic acid-A concentration. Method: Male SD rats were randomized into 5 groups: normal diet control group, low-salt diet control group, Low-, Mid-, and High-dose groups. Renal function and morphological changes in renal tissue were observed at 4 and 6 weeks after treatment with CAME, respectively. The aristolochic acid-A concentration in blood was determined by LC-MS-MS method. Result: Compared with low-salt diet control group, the urine volumes in 3 groups were increased at the 2nd weeks. At the 4th weeks, the urine volumes were decreased; other renal changes in low- and mid-dose groups were not obvious; the levels of urine protein and BUN were remarkably increased in high-dose group. At the 6th weeks, the urine volume was decreased in high-dose group and the levels of urine protein, Crea and BUN were significantly increased. Morphologic changes consisted of vacuolization of renal tubular cells, hyalinization of small arterioles and the light renal interstitial fibrosis. All the injury changes in High-dose group were more severe than those in low- and mid-dose groups. The parameters in two control groups had no statistical significance. The plasma aristolochic acid-A concentration was very low. Conclusion: Long-term use of CAME in rats results in renal function and morphological changes, which correlated with time and dosage of used CAME and might be independence to plasma aristolochic acid-A concentration.