RESUMO
A patented organotin di-n-butyl-di-(4-chlorobenzohydroxamato)tin (DBDCT) with high a antitumor activity was designed, however, its antitumor and toxic mechanisms have not yet been clearly illustrated. Hepatic proteins of DBDCT-treated rats were identified and analyzed using LC-MS/MS with label-free quantitative technology. In total, 149 differentially expressed proteins were successfully identified. Five protein and mRNA expressions were involved in the peroxisome proliferator-activated receptor (PPAR) signaling pathway, including a scavenger receptor (CD36), adipocyte fatty acid binding protein 4 (FABP4), enoyl-CoA hydratase (EHHADH), acetyl-CoA acyltransferase 1 (ACAA1), and phosphoenolpyruvate carboxykinase (PEPCK) in DBDCT-treated Rat Liver (BRL) cells. PPAR-α and PPAR-λ were also significantly decreased at both protein and mRNA levels. Furthermore, compared with the DBDCT treatment group, a special blocking agent of PPAR-λ T0070907 was used to evaluate the relationship between PPAR-λ and its downstream genes. Our studies indicated that DBDCT may serve as a modulator of PPAR-λ, further up-regulating CD36, FABP4 and EHHADH on the PPAR signal pathway.
Assuntos
Fígado/metabolismo , Fígado/patologia , Compostos Orgânicos de Estanho/toxicidade , PPAR alfa/metabolismo , Proteômica/métodos , Transdução de Sinais/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Antígenos CD36/metabolismo , Caspases/metabolismo , Linhagem Celular , Ativação Enzimática/efeitos dos fármacos , Proteínas de Ligação a Ácido Graxo/metabolismo , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Fígado/efeitos dos fármacos , Compostos Orgânicos de Estanho/química , PPAR alfa/genética , Enzima Bifuncional do Peroxissomo/genética , Enzima Bifuncional do Peroxissomo/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos WistarRESUMO
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, HS90ß 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.