Carcinogenesis, Vol 18, 1695-1700, Copyright © 1997 by Oxford University Press
MR Lovern, MJ Turner, M Meyer, GL Kedderis, WE Bechtold and PM Schlosser
Benzene is a ubiquitous environmental pollutant that is known to cause
hematotoxicity and leukemia in humans. The initial oxidative metabolite of
benzene has long been suspected to be benzene oxide (3,5-
cyclohexadiene-1,2-oxide). During in vitro experiments designed to
characterize the oxidative metabolism of [14C]benzene, a metabolite was
detected by HPLC-radioactivity analysis that did not elute with other known
oxidative metabolites. The purpose of our investigation was to prove the
hypothesis that this metabolite was benzene oxide. Benzene (1 mM) was
incubated with liver microsomes from human donors, male B6C3F1 mice, or
male Fischer-344 rats, NADH (1 mM), and NADPH (1 mM) in 0.1 M sodium
phosphate buffer (pH 7.4) and then extracted with methylene chloride. Gas
chromatography-mass spectrometry analysis of incubation extracts for mice,
rats, and humans detected a metabolite whose elution time and mass spectrum
matched that of synthetic benzene oxide. The elution time of the benzene
oxide peak was approximately 4.1 min, while phenol eluted at approximately
8 min. Benzene oxide also coeluted with the HPLC peak of the previously
unidentified metabolite. Based on the 14C activity of this peak, the
concentration of benzene oxide was determined to be approximately 18
microM, or 7% of total benzene metabolites, after 18 min of incubation of
mouse microsomes with 1 mM benzene. The metabolite was not observed in
incubations using heat- inactivated microsomes. This is the first
demonstration that benzene oxide is a product of hepatic benzene metabolism
in vitro. The level of benzene oxide detected suggests that benzene oxide
is sufficiently stable to reach significant levels in the blood of mice,
rats, and humans and may be translocated to the bone marrow. Therefore
benzene oxide should not be excluded as a possible metabolite involved in
benzene-induced leukemogenesis.
ARTICLES
Identification of benzene oxide as a product of benzene metabolism by mouse, rat, and human liver microsomes
Biomathematics Program, North Carolina State University, Raleigh, USA.
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