Kalia Kiran, Narula Gagan Deep, Kannan G M, Flora S J S
Department of Biosciences, Sardar Patel University, Vallabh Vidyanagar-388001, Gujarat, India.
Comp Biochem Physiol C Toxicol Pharmacol. 2007 Jan;144(4):372-9. doi: 10.1016/j.cbpc.2006.11.001. Epub 2006 Nov 17.
We compared the therapeutic efficacy of captopril and a thiol chelating agent, meso 2,3-dimercaptosuccinic acid (DMSA) either individually or in combination against arsenite induced oxidative stress and mobilization of metal in rats. Animals were exposed to 100 ppm arsenite as sodium arsenite in drinking water for six weeks followed by treatment with DMSA (50 mg/kg, orally), captopril (50 mg/kg, intraperitoneally) either alone or in combination, once daily for 5 consecutive days. Arsenite exposure led to a significant depletion of blood delta-aminolevulinic acid dehydratase (ALAD) activity, glutathione and platelet levels while significantly increased the level of reactive oxygen species (in RBCs). Hepatic reduced glutathione (GSH) level showed a significant decrease while, thiobarbituric acid reactive substances (TBARS) levels increased on arsenite exposure indicating arsenite induced hepatic oxidative stress. Kidney GSH, GSSG, catalase and TBARS remained unchanged on arsenite exposure. Treatment with DMSA was effective in increasing ALAD activity while, captopril was ineffective when given alone. Captopril when co-administered with DMSA also provided no additional beneficial effect on blood ALAD activity but significant brought altered platelet counts back to the normal value. In contrast, administration of captopril alone provided significant beneficial effects on hepatic oxidative stress, and in combination with DMSA provided a more pronounced recovery in the TBARS level compared to the individual effect of DMSA and captopril. Renal biochemical variables remained insensitive to arsenite and any of the treatments. Interestingly, combined administration of captopril with DMSA had a remarkable effect in depleting total arsenic concentration from blood and soft tissues. These results lead us to conclude that captopril administration during chelation treatment had some beneficial effects particularly on the protection of inhibited blood ALAD activity, and depletion of arsenic level. The study supports our earlier conclusion that a co-administration of an antioxidant is more beneficial than monotherapy with the chelating agents, in order to achieve optimal effects of chelation in arsenite toxicity.
我们比较了卡托普利和一种硫醇螯合剂——内消旋2,3 - 二巯基丁二酸（DMSA）单独或联合使用对亚砷酸盐诱导的大鼠氧化应激和金属动员的治疗效果。动物饮用含100 ppm亚砷酸钠的水六周，随后分别用DMSA（50 mg/kg，口服）、卡托普利（50 mg/kg，腹腔注射）单独或联合给药，连续5天，每天一次。亚砷酸盐暴露导致血液δ-氨基乙酰丙酸脱水酶（ALAD）活性、谷胱甘肽和血小板水平显著降低，而红细胞中活性氧水平显著升高。肝脏还原型谷胱甘肽（GSH）水平显著下降，而硫代巴比妥酸反应性物质（TBARS）水平在亚砷酸盐暴露时升高，表明亚砷酸盐诱导了肝脏氧化应激。亚砷酸盐暴露时，肾脏的GSH、GSSG、过氧化氢酶和TBARS保持不变。DMSA治疗可有效提高ALAD活性，而单独使用卡托普利则无效。卡托普利与DMSA联合使用时，对血液ALAD活性也没有额外的有益作用，但能显著使血小板计数恢复到正常水平。相比之下，单独使用卡托普利对肝脏氧化应激有显著的有益作用，与DMSA联合使用时，与DMSA和卡托普利单独使用的效果相比能使TBARS水平有更明显的恢复。肾脏生化指标对亚砷酸盐和任何一种治疗均不敏感。有趣的是，卡托普利与DMSA联合给药对降低血液和软组织中的总砷浓度有显著效果。这些结果使我们得出结论，螯合治疗期间给予卡托普利有一些有益作用，特别是对保护受抑制的血液ALAD活性和降低砷水平。该研究支持了我们之前的结论，即联合使用抗氧化剂比单独使用螯合剂进行单一疗法更有益，以便在亚砷酸盐中毒时实现螯合的最佳效果。
