Abdel-Aziz A A, Abdel-Rahman S Z, Nouraldeen A M, Shouman S A, Loh J P, Ahmed A E
Department of Biochemistry and Pharmacology, Faculty of Pharmacy, Al-Azhar University, Cairo, Egypt.
Reprod Toxicol. 1993 May-Jun;7(3):263-72. doi: 10.1016/0890-6238(93)90233-w.
Binding of haloacetonitriles or their reactive metabolites to macromolecules of fetal tissue may be responsible for reproductive toxicity. To investigate the role of glutathione (GSH) in the metabolism and reproductive toxicity of haloacetonitriles, irreversible interaction of chloroacetonitrile (CAN) with maternal uterine and fetal DNA was assessed in a time course study among normal and among glutathione-depleted mice treated with [2-14C]-CAN. GSH was depleted in maternal and fetal tissues by treating of animals with diethylmaleate (DEM) 1 h before [2-14C]-CAN administration. Maternal urinary excretion of thiocyanate was 5 times higher in glutathione-depleted mice than in controls. At 8 and 24 h following [2-14C]-CAN administration, total radioactivity uptake in maternal uterine tissue, amniotic fluid, and fetal tissue was higher in glutathione-depleted mice than in control. Also the interaction of CAN or its reactive metabolites with maternal uterine DNA was enhanced following glutathione depletion. At 24 h after treatment, the covalent binding to DNA in fetal tissue was significantly increased in glutathione depleted mice (205% of control). The magnitude of interaction of CAN in fetal DNA was about 4 times higher than that in uterine DNA. The time course study in either maternal uterine or fetal DNA revealed elevated and persistent levels of covalent binding of [ C]-CAN to DNA at 72 h after treatment. Enhancement of the molecular interaction of CAN in maternal and fetal DNA following GSH depletion indicates an important role for GSH in CAN metabolism.
卤代乙腈或其活性代谢产物与胎儿组织大分子的结合可能是生殖毒性的原因。为了研究谷胱甘肽（GSH）在卤代乙腈代谢和生殖毒性中的作用，在一项时间进程研究中，评估了氯乙腈（CAN）与正常小鼠以及用[2-¹⁴C]-CAN处理的谷胱甘肽耗竭小鼠的母体子宫和胎儿DNA的不可逆相互作用。在给予[2-¹⁴C]-CAN前1小时，用马来酸二乙酯（DEM）处理动物，使母体和胎儿组织中的GSH耗竭。谷胱甘肽耗竭小鼠的母体尿中硫氰酸盐排泄量比对照组高5倍。在给予[2-¹⁴C]-CAN后8小时和24小时，谷胱甘肽耗竭小鼠的母体子宫组织、羊水和胎儿组织中的总放射性摄取量高于对照组。谷胱甘肽耗竭后，CAN或其活性代谢产物与母体子宫DNA的相互作用也增强。处理后24小时，谷胱甘肽耗竭小鼠胎儿组织中与DNA的共价结合显著增加（为对照组的205%）。CAN在胎儿DNA中的相互作用程度比在子宫DNA中高约4倍。母体子宫或胎儿DNA的时间进程研究显示，处理后72小时，[¹⁴C]-CAN与DNA的共价结合水平升高且持续存在。GSH耗竭后CAN在母体和胎儿DNA中分子相互作用的增强表明GSH在CAN代谢中起重要作用。
