EFFECT OF GLUTATHIONE MODULATION ON MOLECULAR INTERACTION OF [C-14] CHLOROACETONITRILE WITH MATERNAL AND FETAL DNA IN MICE

Binding of haloacetonitriles or their reactive metabolites to macromol ecules of fetal tissue may be responsible for reproductive toxicity. T o investigate the role of glutathione (GSH) in the metabolism and repr oductive toxicity of haloacetonitriles, irreversible interaction of ch loroacetonitrile (CAN) with maternal uterine and fetal DNA was assesse d in a time course study among normal and among glutathione-depleted m ice treated with [2-C-14]-CAN. GSH was depleted in maternal and fetal tissues by treating of animals with diethylmaleate (DEM) 1 h before [2 -C-14]-CAN administration. Maternal urinary excretion of thiocyanate w as 5 times higher in glutathione-depleted mice than in controls. At 8 and 24 h following [2-C-14]-CAN administration, total radioactivity up take in maternal uterine tissue, amniotic fluid, and fetal tissue was higher in glutathione-depleted mice than in control. Also the interact ion of CAN or its reactive metabolites with maternal uterine DNA was e nhanced 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 interac tion 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 re vealed elevated and persistent levels of covalent binding of [C-14]-CA N to DNA at 72 h after treatment. Enhancement of the molecular interac tion of CAN in maternal and fetal DNA following GSH depletion indicate s an important role for GSH in CAN metabolism.