Comparative studies on the metabolism and mutagenicity of vinyl ethers

4-Nitrophenyl vinyl ether (1), umbelliferyl vinyl ether (2), 4-cyanophenyl vinyl ether (3), and 4-acetylphenyl vinyl ether (4) were mutagenic toward Salmonella typhimurium TA100 and TA100NR in the presence of the hepatic 9000 x g supernatant fraction fortified with a reduced nicotinamide adenine dinucleotide phosphate generating system (S9mix), but no significant mutagenicity of 4-chlorophenyl vinyl ether (5), phenyl vinyl ether (6), n-butyl vinyl ether (7), and ethyl vinyl ether (8) was found. The epoxides of 1-4 were highly mutagenic toward the bacteria without the S9mix. Also, epoxides of 5 and 6 showed relatively weak mutagenicity. Studies on the metabolism of 1 showed that the epoxide (1a) formed from 1 by microsomes behaved as a labile intermediate in the incubation mixture. Untreated rat hepatic microsomes accumulated 1a and induced mutagenicity of 1 most effectively among the activation systems used. Mutagenic activities of vinyl ethers in the presence of the S9mix were correlated with stabilities of their epoxides. From these results, it is suggested that the critical factor for the mutagenicity of vinyl ethers is the formation and stability of epoxide intermediate in the biological system.