Carcinogenesis, Vol 18, 1637-1641, Copyright © 1997 by Oxford University Press
AB Lindstrom, K Yeowell-O'Connell, S Waidyanatha, BT Golding, R Tornero-Velez and SM Rappaport
Although it is generally assumed that metabolism of benzene proceeds
through an initial step involving oxidation to benzene oxide (BO) by CYP450
in the liver, the production of BO has never been unambiguously confirmed
in animals dosed with benzene. Furthermore, prevailing hypotheses of the
mechanism by which benzene causes cancer have ignored the possibility that
BO might play a direct role, despite the fact that BO is electrophilic,
binds covalently to cell macromolecules and is presumably genotoxic. A
likely reason for this lack of attention to the role of BO in the
carcinogenesis of benzene is the presumption that this epoxide is too
reactive to escape the hepatocyte after it is formed. We employed gas
chromatography-mass spectrometry to measure BO in the blood of F344 rats,
both in vitro and up to 24 h following oral administration of benzene.
Surprisingly, BO was relatively stable in rat blood at 37 degrees C
(estimated half-life = 7.9 min) and, after administering a single dosage of
400 mg benzene/kg body wt, a blood concentration of 90 nM BO (8.5 ng/ml)
was measured for approximately 9 h. Using a published PBPK model we
estimate that approximately 4.3% of the metabolized dose of benzene was
released as BO from the liver into blood. This confirms that BO is, indeed,
formed from metabolism of benzene and is sufficiently stable to be
distributed throughout the body at levels which are likely to be greater
than those of the other electrophilic benzene metabolites.
ARTICLES
Measurement of benzene oxide in the blood of rats following administration of benzene
Department of Environmental Sciences and Engineering, School of Public Health, University of North Carolina at Chapel Hill, 27599-7400, USA.
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