Comparison of toxic reaction of Tripterygium wilfordii multiglycoside in normal and adjuvant arthritic rats
Comparison of toxic reaction of Tripterygium wilfordii multiglycoside in normal and adjuvant arthritic rats
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DOI：
10.1016/j.jep.2011.03.007
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发表时间：
2011-05-17
影响因子：
5.4
通讯作者：
Lu, Aiping
中科院分区：
文献类型：
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作者：
Li, Jian;Lu, Yongheng;Lu, Aiping
研究目的：雷公藤多苷（雷公藤多苷）是一种获批的中成药，用于治疗类风湿关节炎等免疫疾病。本研究旨在探讨GTW对佐剂性关节炎大鼠（AA大鼠）的毒性反应是否与正常大鼠不同。材料与方法：采用右后足部注射完全弗氏佐剂免疫雄性SD大鼠，制备大鼠关节炎模型。免疫后第15天至第28天，以7或105 mg kg（-1）天灌胃给药GTW。检查常规临床参数及肝、肾、睾丸组织病理变化。采用LC-MS分析各组血清代谢谱。结合质谱（MS）数据集进行主成分分析（PCA）和偏最小二乘判别分析（PLS-DA）。所有定量数据均采用双因素方差分析，采用Student’st检验。结果与结论：两种剂量的GTW治疗均能减轻左、右后腿肿胀。高剂量GTW对正常大鼠肝组织有轻微的脂质变性，而GTW对AA大鼠肝组织无明显病理改变。与给予GTW的正常大鼠相比，血清丙氨酸转氨酶（ALT）、肌酐（CRE）和血尿素氮（BUN）水平无统计学差异。然而，与相同条件下的正常大鼠相比，GTW对AA大鼠血清中谷草转氨酶（AST）水平显著降低（p < 0.05），说明GTW对AA大鼠和正常大鼠的肝毒性作用不同。代谢分析显示正常大鼠PCA与PLS-DA评分点明显分离，低剂量GTW扰动AA大鼠PCA与PLS-DA评分点无分离。结果表明，小剂量GTW对正常大鼠有全身毒性，对AA大鼠无全身毒性。生物标志物分析显示，与正常大鼠相比，暴露于GTW下AA大鼠溶血磷脂酰胆碱（LPCs）水平下调，而熊去氧胆酸（UDCA）和鹅去氧胆酸（CDCA）水平上调。根据代谢标志物的通路分析，我们认为LPC。UDCA和CDCA是胆碱和脂肪酸代谢的关键中间体。脂质代谢是生理状态动物肝毒性的相关结果。综上所述，GTW在正常大鼠和AA大鼠之间可引起不同的毒性反应，脂质代谢可能是导致肝脂质沉积或其他肝损伤的机制之一。爱思唯尔爱尔兰有限公司版权所有。版权所有。
Aim of the study: Tripterygium wilfordii multiglycoside (GTW), an authorized Chinese patent drug, is used for treatment of rheumatoid arthritis and other immune disease. This study was to determine whether GTW induced different toxic reactions in adjuvant arthritis rats (AA rats) compared to those in normal rats.Materials and methods: To prepare arthritic rat model, male Sprague-Dawley (SD) rats were immunized by injecting complete Freund's Adjuvant into right hind footpad. And then, GTW was given to rats intra-gastrically at dosage of 7 or 105 mg kg(-1) day(-1) from day 15 to day 28 after immunization. Routine clinical parameters and histopathologic changes of liver, kidney and testis were examined. Metabolic profiling in serum of groups was analyzed by LC-MS. A principal component analysis (PCA) and partial-least-squares discriminate analysis (PLS-DA) were carried out combined with mass spectrometry (MS) data set. All the quantitative data were performed by two-way ANOVA analysis following Student's t-test.Results and conclusions: Treatment with GTW at both doses could diminish the right and left hind paws swelling. There was slight lipoid degeneration in hepatic tissue of normal rats treated by high dose of GTW, but there were not distinctly pathological changes in hepatic tissue of AA rats treated by GTW. Compared normal rats administered with GTW, no statistically significant difference in the serum alanine aminotransferase (ALT), creatinine (CRE), and blood urea nitrogen (BUN) levels were observed. However, the serum aspartate aminotransferase (AST) level was significant decreased in AA rats under exposure GTW compared with normal rats in the same conditions (p < 0.05), which indicated that GTW could offer a different liver toxic reaction in normal and AA rats. The metabolic analysis showed that a clear separation of PCA and PLS-DA score spot in normal rats, but not separation was seen in AA rats perturbed with low dosage GTW. The result indicated low dosage GTW might arouse a general toxic in normal rats but not in AA rats. The biomarker analysis showed that the level of lysophosphatidylcholines (LPCs) was down-regulated, but the level of ursodeoxycholic acid (UDCA) and chenodexycholic acid (CDCA) was up-regulated in AA rats compared with normal rats under exposure GTW. According to pathway analysis of metabolic markers, we conceived that LPC. UDCA and CDCA were the critical intermediates of choline and fatty acid metabolism. And the lipid metabolism was a correlative outcome of GTW induced toxicity in the liver in physiological condition animals. Taken together, GTW could induce different toxic reactions between normal and AA rats, and the lipid metabolism might be part of the mechanism for the hepatic lipidosis or the other liver injury. Crown Copyright (C) 2011 Published by Elsevier Ireland Ltd. All rights reserved.