Kannan Gurusamy M, Flora Swaran J S
Division of Pharmacology and Toxicology, Defence Research and Development Establishment, Jhansi Road, Gwalior-474 002, India.
Biol Trace Elem Res. 2006 Apr;110(1):43-59. doi: 10.1385/BTER:110:1:43.
The present study deals with the therapeutic potential of combined administration of N-acetylcysteine (NAC) along with monoisoamyl DMSA (MiADMSA) against chronic arsenic poisoning in guinea pigs. Animal were exposed to 50 ppm arsenic in drinking water for 8 mo and subsequently treated for 5 consecutive days with 100 mg/kg NAC (orally) and MiADMSA (intraperitoneally), individually or in combination (50 mg/kg each). Arsenic exposure produced a significant depletion of blood delta- aminolevulinic acid dehydrate (ALAD) activity, increased the blood zinc protoporphyrin (ZPP) level, and reduced blood and liver glutathione (GSH) levels in guinea pigs. Hepatic oxidized glutathione (GSSG) and thiobarbituric acid reactive substance (TBARS) levels showed a marked increase, whereas hepatic alkaline phosphatase (ALP) activity decreased and acid phosphatase (ACP) activity increased on arsenic exposure. Significant depletion of liver transaminase activities on arsenic exposure suggests organ injury. Administration of MiADMSA, alone and in combination with NAC after arsenic exposure, was able to significantly enhance hepatic GSH and to reduce GSSG and TBARS levels compared to the arsenic control. Biochemical variables indicative of liver injury generally remained insensitive to any of these treatments. The recoveries in parameters indicative of oxidative stress were more marked in guinea pigs treated with combined administration of NAC and MiADMSA than monotherapy. Interestingly, there was a more pronounced depletion of arsenic from blood and tissues after combined treatment with NAC plus MiADMSA than MiADMSA. Blood and tissues copper, zinc, iron, and calcium concentrations showed a significant increase after arsenic exposure, which showed improvement, particularly after combined administration of MiADMSA and NAC. Based on these data, a proposal can be made that greater effectiveness in chelation treatment against chronic arsenic poisoning (i.e., turnover in the oxidative stress and removed of arsenic from the system) could be achieved by combined administration of an antioxidant (preferably having a thiol moiety) with MiADMSA.
本研究探讨了N-乙酰半胱氨酸（NAC）与单异戊基二巯基丁二酸（MiADMSA）联合给药对豚鼠慢性砷中毒的治疗潜力。将动物置于含50 ppm砷的饮用水中8个月，随后分别或联合（各50 mg/kg）连续5天用100 mg/kg NAC（口服）和MiADMSA（腹腔注射）进行治疗。砷暴露导致豚鼠血液中δ-氨基乙酰丙酸脱水酶（ALAD）活性显著降低，血液锌原卟啉（ZPP）水平升高，血液和肝脏谷胱甘肽（GSH）水平降低。肝脏氧化型谷胱甘肽（GSSG）和硫代巴比妥酸反应性物质（TBARS）水平显著升高，而肝脏碱性磷酸酶（ALP）活性降低，酸性磷酸酶（ACP）活性在砷暴露时升高。砷暴露时肝脏转氨酶活性显著降低表明器官损伤。与砷对照组相比，砷暴露后单独或联合NAC给予MiADMSA能够显著提高肝脏GSH水平，并降低GSSG和TBARS水平。指示肝脏损伤的生化变量通常对任何一种治疗均不敏感。与单一疗法相比，联合给予NAC和MiADMSA治疗的豚鼠中，指示氧化应激的参数恢复更为明显。有趣的是，NAC加MiADMSA联合治疗后，血液和组织中的砷耗竭比MiADMSA更为显著。砷暴露后血液和组织中的铜、锌、铁和钙浓度显著升高，联合给予MiADMSA和NAC后这些指标尤其有所改善。基于这些数据，可以提出这样的建议，即联合给予抗氧化剂（最好含有巯基部分）与MiADMSA，在螯合治疗慢性砷中毒方面（即氧化应激的逆转和从系统中去除砷）可能具有更高的有效性。
