ROLE OF GLUTATHIONE MODULATION IN ACRYLONITRILE INDUCED GASTRIC DNA-DAMAGE IN RATS

Acrylonitrile (VCN) or its reactive metabolites irreversibly interact with gastric DNA in vivo and cause DNA damage. The effect of glutathio ne (GSH) modulation on VCN-induced genotoxicity and unscheduled DNA re pair synthesis (UDRS) in DNA of gastric mucosal tissues was investigat ed. VCN-induced UDRS was determined: in control rats, rats with deplet ed gastric GSH contents, and rats treated with sulfhydryl compounds. A single oral dose (23 mg/kg) of VCN induced a time- and dose-dependent increase in gastric UDRS and decrease in GSH levels. While maximal UD RS in gastric mucosa was observed 2 h following oral administration of 23 mg/kg VCN, maximal GSH depletion (50% of control) was detected 4 h following treatment. Increasing the VCN dose to 46 mg/kg caused a fur ther decrease in gastric GSH level (27% of control), while UDRS was el evated. Inhibition of VCN oxidation by treatment of the animals with t he cytochrome P450 inhibitor, SKF 525-A, prior to VCN administration c aused 65% reduction in VCN-induced UDRS. Treatment of rats with the GS H depletor diethylmaleate (DEM) prior to VCN administration caused 167 % increase in UDRS in gastric mucosal tissues. Treatment of the animal s with the sulfhydryl compounds, cysteine and penicillamine, prior to VCN administration protected against VCN-induced UDRS. The results dem onstrated an inverse and highly significant correlation between gastri c GSH levels and VCN-induced UDRS (r = -0.873, P < 0.0001). In conclus ion, our study indicates that VCN bioactivation and the homeostasis of gastric GSH may play a major role in the initial processes underlying VCN-induced gastric carcinogenesis.