Ban M, Hettich D, Huguet N, Cavelier L
Service Toxicologie Industrielle Expérimentale, Institut National de Recherche et de Sécurité, Vandoeuvre, France.
Toxicol Lett. 1995 Jul;78(2):87-92. doi: 10.1016/0378-4274(94)03237-2.
Male Swiss OF1 mice were administered orally with a single dose (200 mg/kg) of 1,1-dichloroethylene (DCE). Examination of cryostat kidney sections stained for alkaline phosphatase (APP) revealed damage to about 50% of the proximal tubules at 8 h following DCE administration. Pretreatment with the anionic transport inhibitor probenecid by i.p., (0.75 mmol/kg, 30 min prior to and 10 min and 5 h following DCE administration) and with the gamma-glutamyltranspeptidase (GGT) inactivator acivicin by gavage and i.p. (50 mg/kg, 1 h and 30 min prior to DCE administration) failed to prevent DCE-induced renal toxicity. Pretreatment with the beta-lyase inactivator amino-oxyacetic acid (AOAA) by gavage (100 mg/kg, 30 min prior to and 10 min and 5 h following DCE administration), and with the renal cysteine conjugate S-oxidase inhibitor methimazole by i.p. (40 mg/kg, 30 min prior to DCE administration) reduced the number of damaged tubules by approximately 50 and 60%, respectively in mice treated with DCE. The results suggest that the DCE undergoes biotransformation by NADPH-cytochrome P450 to several reactive species which conjugate with glutathione (GSH). After arriving in the kidneys, the resulting conjugates reach the renal cells by a mechanism which depends on neither GGT, nor on an anionic transport system which is sensitive to probenecid. Once in the cells, the presumed GSH conjugates and/or their derivatives undergo secondary modification by beta-lyase and cysteine conjugate S-oxidase to reactive metabolite(s).
给雄性瑞士OF1小鼠口服单剂量（200毫克/千克）的1,1 - 二氯乙烯（DCE）。对经碱性磷酸酶（APP）染色的低温恒温器肾脏切片进行检查发现，在给予DCE后8小时，约50%的近端小管受到损伤。通过腹腔注射（0.75毫摩尔/千克，在给予DCE前30分钟以及给予DCE后10分钟和5小时）用阴离子转运抑制剂丙磺舒进行预处理，以及通过灌胃和腹腔注射（50毫克/千克，在给予DCE前1小时和30分钟）用γ-谷氨酰转肽酶（GGT）灭活剂阿西维辛进行预处理，均未能预防DCE诱导的肾毒性。通过灌胃（100毫克/千克，在给予DCE前30分钟以及给予DCE后10分钟和5小时）用β-裂解酶灭活剂氨基氧乙酸（AOAA）进行预处理，以及通过腹腔注射（40毫克/千克，在给予DCE前30分钟）用肾半胱氨酸结合物S-氧化酶抑制剂甲巯咪唑进行预处理，在用DCE处理的小鼠中，受损小管的数量分别减少了约50%和60%。结果表明，DCE通过NADPH - 细胞色素P450进行生物转化为几种与谷胱甘肽（GSH）结合的反应性物质。到达肾脏后，产生的结合物通过一种既不依赖GGT也不依赖对丙磺舒敏感的阴离子转运系统的机制到达肾细胞。一旦进入细胞，推测的GSH结合物和/或其衍生物通过β-裂解酶和半胱氨酸结合物S-氧化酶进行二次修饰形成反应性代谢物。
