Metabolic basis of benzene toxicity

Abstract

Potential metabolic mechanisms underlying the haemopoietic toxicity of benzene include bioactivation of phenolic metabolites of benzene by peroxidases in bone marrow and ring opening reactions to generate muconate derivatives. Peroxidase-mediated activation of phenolic metabolites of benzene generates reactive quinones which can be detoxified by NAD(P)H:quinone acceptor oxidoreductase (NQO1). The major peroxidase enzyme 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 expressed 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 benzene resulting in aberrant haemopoiesis. A polymorphism in NQO1 is also described which leads to a complete lack of NQO1 activity. The toxicological significance of this polymorphism with respect to benzene toxicity is under investigation.