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Investigation of Benzene Oxide in Bone Marrow and Other Tissues of F344 Rats Following Metabolism of Benzene in Vitro and in Vivo

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Abstract: This study examines the initial activation of benzene, exploring key aspects of its metabolism by measurement of benzene oxide (BO) and BO-protein adducts in vitro and in vivo. To assess the potential influence of various factors on the production of BO, microsomes were prepared from tissues that were either targets of benzene toxicity, i.e. the bone marrow and Zymbal glands, or not targets, i.e. liver and kidneys, of control and acetone-treated F344 rats. No BO or phenol was detected in microsomal preparations of bone marrow or Zymbal glands (less than 0.007 nmol BOmg protein and 0.7 nmol phenol mg protein). On the other hand. BO and phenol were readily detected in preparations of liver and kidney microsomes and acetone pretreatment resulted in a 2-fold (kidney) increase or 3.7-fold (liver) increase in production of these metabolites. Initial rates of BO production in the liver isolates were 30 (control) to 50 (acetone-treated) times higher than in the corresponding kidney tissues. The estimated half-life of BO in bone marrow homogenates was 6.0 min and the second-order reaction rate constant was estimated to be 1.35 x 10-3 1 (g bone marrow)-1 (h)-1. These kinetic constants were used with measurements of BO-bone marrow adducts in F344 rats, receiving a single gavage dosage of 50-400 mg benzene (kg body weight)-1(McDonald, T.M., et al. (1994), Cancer Res. 54, 4907-4914), to predict the bone marrow dose of BO. Among the rats receiving 400 mg (kg body weight)-1, a BO dose of 1.13 x 103 nM BO-h was estimated for the bone marrow, or roughly 40% of the corresponding blood dose predicted from BO-albumin adducts. Together these data suggest that, although BO is not produced at detectable levels in the bone marrow or Zymbal glands of F344 rats, BO is rapidly distributed via the bloodstream to these tissues where it may play a role in toxicity.

This work was supported by the National Institute of Environmental Health Sciences through grant P42ES05948. 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 or recommendation for use.
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Citation:Lindstrom, A. B., K. Yeowello'connell, S. Waidyanatha, T. A. Mcdonald, and S. M. Rappaport. Investigation of Benzene Oxide in Bone Marrow and Other Tissues of F344 Rats Following Metabolism of Benzene in Vitro and in Vivo. CHEMICO-BIOLOGICAL INTERACTIONS 122(1):41-58, (1999).
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Contact: Liz Hope - (919) 541-2785 or hope.elizabeth@epa.gov
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Division: Human Exposure & Atmospheric Sciences Division
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Branch: Human Exposure Analysis Branch
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Product Type: Journal
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Published: 08/01/1999
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