Modulation of the toxicity and macromolecular binding of benzene metabolites by NAD(P)H : Quinone oxidoreductase in transfected HL-60 cells

Benzene is oxidized in the liver to produce a series of hydroxylated metabo lites, including hydroquinone and 1,2,4-benzenetriol. These metabolites are activated to toxic and genotoxic species in the bone marrow via oxidation by myeloperoxidase (MPO). NAD(P)H:quinone oxidoreductase (NQO1) is an enzym e capable of reducing the oxidized quinone metabolites and thereby potentia lly reducing their toxicities. We introduced the NQO1 gene into the HL-60 c ell line to create a high MPO-, high NQO1-expressing cell line, and tested its response in assays of benzene metabolite toxicity. NQO1 expression redu ced a class of hydroquinone- and benzenetriol-induced DNA adducts by 79-86% . The cytotoxicity and apoptosis caused by hydroquinone were modestly reduc ed, while protein binding was unchanged and the rate of glutathione depleti on increased. NQO1's activity in reducing a class of benzene metabolite-ind uced DNA adducts may be related to its known activities in maintaining memb rane-bound endogenous antioxidants in reduced form. Alternatively, NQO1 act ivity may prevent the formation of adducts which result from polymemized pr oducts of the quinones. In either case, this protection by NQO1 may be an i mportant mechanism in the observation that a lack of NQO1 activity affords an increased risk of benzene poisoning in exposed individuals.