The electrophilic, mutagenic and tumorigenic activities of phenyl and 4-nitrophenyl vinyl ethers and their epoxide metabolites

Abstract

The metabolism and mutagenicity of phenyl and 4-nitrophenyl vinyl ethers (PVE and NPVE) and their epoxide metabolites, phenoxyoxirane (PO) and 2'-(4-nitro-phenoxy)oxirane (NPO), were studied including reactions with DNA and tests for carcinogenicity. PVE and NPVE were epoxidized in dry acetone by dimethyldioxirane to give high yields (95%) of the pure epoxides. The epoxides are unstable in aqueous media and in 0.1 N phosphate buffer, pH 7.4, at 37 degrees C; they had half-lives of 2.7 min (PO) and 4.4 min (NPO). These times were reduced to 1.9 min (PO) and 2.5 min (NPO) in the presence of isotonic (154 mM) chloride ion. In neutral phosphate buffer these epoxides hydrolyze to form glycolaldehyde and the corresponding phenols; in the presence of chloride ion, chloroacetaldehyde and several unknown compounds are also formed. Glycolaldehyde was also found as a hydrolysis product of the presumed epoxides generated in the hepatic microsomal oxidation of PVE and NPVE. PO and NPO reacted with DNA to form adducts that depurinated in weak acid to form 7-(2'-oxoethyl)guanine and N(2),3-ethenoguanine. PO was weakly mutagenic in Salmonella typhimurium TA1535 while NPO was much more mutagenic under the same conditions. PO and NPO were found to have mutagenic 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 initiating doses followed by multiple doses of phorbol ester (TPA). NPO was a stronger tumor initiator than PO. NPO had appreciable activity as an initiator of hepatoma formation in infant male B6C3F1 mice. Thus PO and NPO are electrophilic, mutagenic and tumorigenic metabolites of their corresponding phenyl vinyl ethers.