Tang Li, Luo Jie-Ran, Li Yun-Lan, Ge Rui, Li Qing-Shan
School of Pharmaceutical Science, Shanxi Medical University, Taiyuan 030001, PR China.
School of Pharmaceutical Science, Shanxi Medical University, Taiyuan 030001, PR China; Shanxi University of Traditional Chinese Medicine, Taiyuan 030024, PR China.
Environ Toxicol Pharmacol. 2017 Apr;51:38-44. doi: 10.1016/j.etap.2017.01.012. Epub 2017 Feb 24.
Di-n-butyl-di-(4-chlorobenzohydroxamato)tin(IV) (DBDCT) is an anti-tumour organotin(IV) compound with hepatotoxicity. To investigate the hepatotoxicity and mechanisms of DBDCT in vivo, proteomic technology 2D gel combined with MALDI-TOF-MS was used in our research. Results indicated that DBDCT increased AST, AKP and ACP activities and decreased ALT activity. Further, sporadic eosinophilic changes and nuclear pyknosis were visible in hepatic pathological observation. Proteomic analysis showed that twenty-two proteins involved in amino acid, nucleic acid, carbohydrate and lipid metabolism, stress response, multicellular organism development and cell apoptosis were differentially expressed and identified. Notably, a considerable amount of the altered proteins, such as OAT, HPPD, M2GD, GSTM2, Glud1, GSTa, HS90β and PDIA3 participated in multi-metabolic pathways and oxidative stress reactions. Our findings indicated that the inhibition of enzyme activity and oxidative stress were the major mechanisms by which DBDCT induced hepatotoxicity, and the altered proteins could be potential drug targets for the further design of new type of organic tin with high activity and low toxicology.
二正丁基-二-(4-氯苯甲酰异羟肟酸根)锡(IV)（DBDCT）是一种具有肝毒性的抗肿瘤有机锡(IV)化合物。为了研究DBDCT在体内的肝毒性及其机制，我们的研究采用了蛋白质组学技术二维凝胶电泳结合基质辅助激光解吸电离飞行时间质谱。结果表明，DBDCT可使谷草转氨酶（AST）、碱性磷酸酶（AKP）和酸性磷酸酶（ACP）活性升高，谷丙转氨酶（ALT）活性降低。此外，肝脏病理观察可见散在嗜酸性变及核固缩。蛋白质组学分析表明，22种参与氨基酸、核酸、碳水化合物和脂质代谢、应激反应、多细胞生物体发育及细胞凋亡的蛋白质存在差异表达并被鉴定。值得注意的是，大量变化的蛋白质，如OAT、HPPD、M2GD、GSTM2、Glud1、GSTa、HS90β和PDIA3参与了多种代谢途径和氧化应激反应。我们的研究结果表明，酶活性抑制和氧化应激是DBDCT诱导肝毒性的主要机制，这些变化的蛋白质可能成为进一步设计高活性、低毒理学新型有机锡的潜在药物靶点。
