MOLECULAR INTERACTION OF [2,3-C-14] ACRYLONITRILE WITH DNA IN GASTRIC TISSUE OF RAT

Acrylonitrile (VCN) is used extensively in polymer industries, and is known to induce gastric cancer following oral administration. A paucity of information exists regarding the mechanism(s) by which acrylonitrile induces gastric neoplasia. The time course for uptake of radioactivity by gastric tissue and covalent binding of [2,3-C-14] VCN or its metabolites to gastric DNA were determined following a single oral dose of 46.5 mg/kg. The rates of DNA synthesis and repair, as measured by unscheduled DNA synthesis in the gastric tissue of VCN-treated rats, were also studied. Maximum tissue uptake and covalent binding of radioactivity to gastric DNA were observed at 15 minutes following [2,3-C-14] VCN administration. At 6 hours following VCN administration, significant inhibition (37% of control) in gastric replicative DNA synthesis was observed. A rebound followed by an increase (211% of control) in replicative DNA synthesis was observed at 24 hours. A three-fold elevation in unscheduled DNA synthesis was observed at 24 hours following treatment with VCN. These results indicate that VCN or its metabolites irreversibly interact with gastric DNA, causing DNA damage. The results also indicate that the delayed VCN-induced DNA repair, determined as unscheduled DNA synthesis, is inefficient for the removal of the resulting DNA lesions.