| Vinyl carbamate (VC) is a metabolite of ethyl carbamate (EC), a chemical found in alcoholic beverages and fermented foods. The carcinogenicity of EC has been attributed to oxidation of EC to VC and subsequently to the VC epoxide, a metabolite that generates DNA adducts. We investigated VC to induce mutagenicity, clastogenicity and carcinogenicity in various tissues including mouse lung and small intestine. VC was mutagenic in the lung and small intestine at doses of 45, 60 and 75 mg/kg, whereas EC was only mutagenic in the lung at 500 and 1000 mg/kg. These results demonstrated that VC and EC are mutagenic in vivo and confirmed that VC is a more potent mutagen than EC. Treatment of mice with diallyl sulfone (DASO 2), a garlic derivative and P450 inhibitor, decreased the VC-induced mutant frequency in the lung by 50-70% and in the small intestine by 41%. Pretreatment of mice with DASO2 Micronucleated reticulocytes were also significantly decreased (33-44%) upon pretreatment with DASO2. In our carcinogenesis study, treatment with DASO2 prior to VC increased survival rates, inhibited lung tumor growth, decreased lung tumor multiplicity and lowered the incidence of mutations in Kras2. Furthermore, frameshifts in the second exon of Kras2 predominated over base substitutions, suggesting that genomic instability may be a contributing factor in VC-induced lung carcinogenesis. Taken together, our findings demonstrated that inhibition of the VC bioactivation pathway by DASO2 resulted in diminution of VC-induced mutagenic, clastogenic and carcinogenic effects. |
