METABOLIC BASIS OF BENZENE TOXICITY

Potential metabolic mechanisms underlying the haemopoietic toxicity of benzene include bioactivation of phenolic metabolites of benzene by p eroxidases in bone marrow and ring opening reactions to generate mucon ate derivatives. Peroxidase-mediated activation of phenolic metabolite s of benzene generates reactive quinones which can be detoxified by NA D(P)H:quinone acceptor oxidoreductase (NQO1). The major peroxidase enz yme in bone marrow is myeloperoxidase (MPO) and potential target cells for phenolic metabolites of benzene were characterized in bone marrow stroma on the basis of high MPO:NQO1 ratios. MPO was found to be expr essed at the level of myeloid progenitor cells in both murine (lineage negative cells) and human (CD34(+) cells) systems. This suggests that progenitor cells may be relevant targets of phenolic metabolites of b enzene resulting in aberrant haemopoiesis. A polymorphism in NQO1 is a lso described which leads to a complete lack of NQO1 activity. The tox icological significance of this polymorphism with respect to benzene t oxicity is under investigation.