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MEASUREMENT OF BENZENE OXIDE IN THE BLOOD OF RATS FOLLOWING ADMINISTRATION OF BENZENE
Citation:
Lindstrom, A B., K. YeowellO'Connell, S. Waidyanatha, B. T. Golding, R TORNERO-VELEZ, AND S. M. Rappaport. MEASUREMENT OF BENZENE OXIDE IN THE BLOOD OF RATS FOLLOWING ADMINISTRATION OF BENZENE. CARCINOGENESIS 18(8):1637-1641, (1997).
Description:
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?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 ~9 h. Using a published PBPK model we estimate that -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.
This work was supported by the National Institute of Environmental Health Sciences through grant P4ES05948. The information in this document has been funded in part by the United States Environmental Protection Agency. It has been subjected to Agency review and approved for publication. Mention of trade names or commercial products does not constitute endorsement of recommendation for use.