基于1H NMR代谢组学方法分析马兜铃酸I诱导的雌雄小鼠急性肾毒性

基于¹H NMR的代谢组学方法, 分析了C57BL/6J小鼠尿样的代谢特征, 揭示出马兜铃酸I(AAI)导致急性肾毒性的分子机理及其在雌性和雄性小鼠上差异的根源. 研究结果表明, AAI的急性肾毒性主要来自AAI给药后抑制了体内的三羧酸(TCA)循环和能量代谢, 破坏了体内肠道菌群的生态平衡, 改变了肾脏细胞内外的渗透压, 从而引起了肾小管的损伤. 代谢模式分析显示雄性小鼠对AAI的肾毒性比雌性小鼠更敏感, 可能源于雄性小鼠本身更低的能量代谢. 结果表明, 基于尿样¹H NMR代谢组学方法有可能为药物的毒性机制和毒性性别差异研究提供新思路.

Metabonomic Study of Aristolochic Acid I-induced Acute Renal Toxicity Urine at Female and Male C57BL/6J Mice Based on 1H NMR

The present work illustrates the metabolic changes of aristolochic acid I-induced acute renal toxicity urine at male and female C57BL/6J mice, which would help to understand the mechanism of renal toxicity and the differences in the metabolism at female and male mice after AAI treatment. The results showed that AAI nephrotoxicity mainly resulted from AAI inhibited the tricaboxylic acid cycle and energy metabolism,damaged the ecology of intestinal flora, changed the osmotic pressure inside and outside the kidney cells, depressed creatinine clearance rate and caused the injury of renal tubular and glomerular. Metabolic pattern analysis also showed that male mice were more sensitive to AAI renal toxicity than the female. These results suggested that urine 1H NMR-based metabonomics probably provides a novel insight into the study of drug toxicity mechanism and the toxicity gender differences.