Investigation of benzene oxide in bone marrow and other tissues of F344 rats following metabolism of benzene in vitro and in vivo

This study examines the initial activation of benzene, exploring key aspect s of its metabolism by measurement of benzene oxide (BO) and BO-protein add ucts in vitro and in vivo. To assess the potential influence of various fac tors on the production of BO, microsomes were prepared from tissues that we re either targets of benzene toxicity, i.e. the bone marrow and Zymbal glan ds, 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 BO:mg protein and 0.7 nmol ph enol/mg protein). On the other hand, BO and phenol were readily detected in preparations of liver and kidney microsomes and acetone pretreatment resul ted in a 2-fold (kidney) increase or 3.7-fold (liver) increase in productio n of these metabolites. Initial rates of BO production in the liver isolate s were 30 (control) to 50 (acetone-treated) times higher than in the corres ponding kidney tissues. The estimated half-life of BO in bone marrow homoge nates was 6.0 min and the second-order reaction rate constant was estimated to be 1.35 x 10(-3) l (g bone marrow)(-1) (h)(-1). These kinetic constants were used with measurements of BO-bone marrow adducts in F344 rats, receiv ing a single gavage dosage of 50-400 mg benzene (kg body weight)(-1) (McDon ald, T.M., et al. (1994), Cancer Res. 54, 4907-4914), to predict the bone m arrow dose of BO. Among the rats receiving 400 mg (kg body weight)(-1), a B O dose of 1.13 x 10(3) nM BO-h was estimated for the bone marrow, or roughl y 40% of the corresponding blood dose predicted from BO-albumin adducts. To gether these data suggest that, although BO is not produced at detectable l evels in the bone marrow or Zymbal glands of F344 rats, BO is rapidly distr ibuted via the bloodstream to these tissues where it may play a role in tox icity. (C) 1999 Elsevier Science Ireland Ltd. All rights reserved.