Wang Quanjun, Jiang Ying, Wu Chunqi, Zhao Jianyu, Yu Shouzhong, Yuan Benli, Yan Xianzhong, Liao Mingyang
Beijing Institute of Pharmacology and Toxicology, 27 Taiping Road, Beijing 100850, PR China.
Toxicol Appl Pharmacol. 2006 Aug 15;215(1):71-82. doi: 10.1016/j.taap.2006.02.012. Epub 2006 Apr 3.
Antiangiogenic compound has been believed to be an ideal drug in the current cancer biological therapy, but the angiogenesis inhibitors suffer setback for unknown toxicity now. A novel synthetic indolin-s-ketone small molecular compound, 3Z-3-[((1)H-pyrrol-2-yl)-methylidene]-1-(1-piperidinylmethyl)-1,3-2H-indol-2-one (Z24) can inhibit angiogenesis in new blood vessels. The hepatotoxicity effects of Z24 oral administration (dosed at 60, 130 and 200 mg/kg) have been investigated in female Wistar rats by using metabonomic analysis of (1)H NMR spectra of urine, plasma and liver extracts, as well as by clinical chemistry analysis, liver histopathology and electron micrographs examination. The (1)H NMR spectra of the biofluids were analyzed visually and via pattern recognition by using principal component analysis. The metabonomic trajectory analysis on the time-related hepatotoxicity of Z24 was carried out based on the (1)H NMR spectra of urine samples, which were collected daily predose and postdose over an 8-day period. Urinary excretion of citrate, lactate, 2-oxo-glutarate and succinate increased following Z24 dosing. Increased plasma levels of lactate, TMAO and lipid were observed, with concomitant decrease in the level of glucose and phosphatidylcholine. Metabolic profiling on aqueous soluble extracts of liver tissues with the high dose level of Z24 showed an increase in lactate and glutamine, together with a decrease in glucose, glycogen and choline. On the other hand, studies on lipid soluble extracts of liver tissues with the high dose level of Z24 showed increased level in lipid triglycerides and decreased level in unsaturated fatty acids and phosphatidylcholine. Moreover, the most notable effect of Z24 on the metabolism was the reduction in the urinary levels of creatinine and TMAO and the increase in acetate, citrate, succinate and 2-oxo-glutamate with time dependence. The results indicate that in rats Z24 inhibits mitochondrial function through altering the energy and lipid metabolism, which results in the accumulation of free fatty acids and lactate because of the lack of aerobic respiration. These data show that the metabonomic approach represents a promising new technology for the toxicological mechanism study.
抗血管生成化合物一直被认为是当前癌症生物治疗中的理想药物，但目前血管生成抑制剂因未知毒性而受挫。一种新型合成吲哚 - s - 酮小分子化合物，3Z - 3 - [((1)H - 吡咯 - 2 - 基)-亚甲基]-1-(1 - 哌啶基甲基)-1,3 - 2H - 吲哚 - 2 - 酮（Z24）能够抑制新生血管中的血管生成。通过对尿液、血浆和肝脏提取物的(1)H NMR光谱进行代谢组学分析，以及临床化学分析、肝脏组织病理学和电子显微镜检查，研究了Z24口服给药（剂量为60、130和200 mg/kg）对雌性Wistar大鼠的肝毒性作用。通过目视检查以及使用主成分分析的模式识别方法对生物流体的(1)H NMR光谱进行分析。基于尿液样本的(1)H NMR光谱，对Z24与时间相关的肝毒性进行代谢组学轨迹分析，尿液样本在给药前和给药后的8天内每天收集。Z24给药后，柠檬酸盐、乳酸盐、2 - 氧代 - 戊二酸盐和琥珀酸盐的尿排泄增加。观察到血浆中乳酸盐、氧化三甲胺（TMAO）和脂质水平升高，同时葡萄糖和磷脂酰胆碱水平降低。高剂量Z24处理的肝脏组织水溶性提取物的代谢谱分析显示乳酸盐和谷氨酰胺增加，同时葡萄糖、糖原和胆碱减少。另一方面，高剂量Z24处理的肝脏组织脂溶性提取物的研究显示脂质甘油三酯水平升高，不饱和脂肪酸和磷脂酰胆碱水平降低。此外，Z24对代谢最显著的影响是肌酐和TMAO的尿水平降低，以及乙酸盐、柠檬酸盐、琥珀酸盐和2 - 氧代 - 谷氨酸盐随时间依赖性增加。结果表明，在大鼠中Z24通过改变能量和脂质代谢抑制线粒体功能，由于缺乏有氧呼吸导致游离脂肪酸和乳酸盐积累。这些数据表明代谢组学方法是毒理学机制研究中一种有前景的新技术。
