Carcinogenesis, Vol 18, 431-437, Copyright © 1997 by Oxford University Press
KK Park, Y Sohn, A Liem, HJ Kim, BC Stewart and JA Miller
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.
ARTICLES
The electrophilic, mutagenic and tumorigenic activities of phenyl and 4- nitrophenyl vinyl ethers and their epoxide metabolites
McArdle Laboratory for Cancer Research, University of Wisconsin Medical School, Madison 53706, USA.
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