THE ELECTROPHILIC, MUTAGENIC AND TUMORIGENIC ACTIVITIES OF PHENYL AND4-NITROPHENYL VINYL ETHERS AND THEIR EPOXIDE METABOLITES

The metabolism and mutagenicity of phenyl and 4-nitrophenyl vinyl ethe rs (PVE and NPVE) and their epoxide metabolites, phenoxyoxirane (PO) a nd 2'-(4-nitrophenoxy)oxirane (NPO), were studied including reactions with DNA and tests for carcinogenicity. PVE and NPVE were epoxidized i n dry acetone by dimethyldioxirane to give high yields (95%) of the pu re epoxides, The epoxides are unstable in aqueous media and in 0.1 N p hosphate buffer, pH 7.4, at 37 degrees C; they had half-lives of 2.7 m in (PO) and 4.4 min (NPO), These times were reduced to 1.9 min (PO) an d 2.5 min (NPO) in the presence of isotonic (154 mM) chloride ion, In neutral phosphate buffer these epoxides hydrolyze to form glycolaldehy de and the corresponding phenols; in the presence of chloride ion, chl oroacetaldehyde and several unknown compounds are also formed, Glycola ldehyde was also found as a hydrolysis product of the presumed epoxide s generated in the hepatic microsomal oxidation of PVE and NPVE. PO an d NPO reacted with DNA to form adducts that depurinated in weak acid t o form 7-(2'-oxoethyl)guanine and N-2,3-ethenoguanine, PO was weakly m utagenic in Salmonella typhimurium TA1535 while NPO was much more muta genic under the same conditions, PO and NPO were found to have mutagen ic half-lives that matched their chemical half-lives. PO and NPO were found to be tumorigenic in the skin of mice after single or five initi ating doses followed by multiple doses of phorbol ester (TPA). NPO was a stronger tumor initiator than PO, NPO had appreciable activity as a n initiator of hepatoma formation in infant male B6C3F(1) mice, Thus P O and NPO are electrophilic, mutagenic and tumorigenic metabolites of their corresponding phenyl vinyl ethers.