A potential mechanism underlying the increased susceptibility of individuals with a polymorphism in NAD(P)H : quinone oxidoreductase 1 (NQO1) to benzene toxicity

NAD(P)H:quinone oxidoreductase 1 (NQO1) is a two-electron reductase that de toxifies quinones derived from the oxidation of phenolic metabolites of ben zene. A polymorphism in NQO1, a C609T substitution, has been identified, an d individuals homozygous for this change (T/T) have no detectable NQO1. Exp osed workers with a T/T genotype have an increased risk of benzene hematoto xicity. This finding suggests NQO1 is protective against benzene toxicity, which is difficult to reconcile with the lack of detectable NQO1 in human b one marrow. The human promyeloblastic cell line, KG-la, was used to investi gate the ability of the benzene metabolite hydroquinone (HQ) to induce NQO1 . A concentration-dependent induction of NQO1 protein and activity was obse rved in I(G-la cells cultured with HQ. Multiple detoxification systems, inc luding NQO1 and glutathione protect against benzene metabolite-induced toxi city. Indeed, exposure to a noncytotoxic concentration of HQ induced both N QO1 and soluble thiols and protected against HQ-induced apoptosis. NQO1 pro tein and activity increased in-wild-type human bone marrow cells (C/C) expo sed to IIO, whereas no NQO1 was induced by HQ in bone marrow cells with the T/T genotype. Intermediate induction of NQO1 by HQ was observed in heteroz ygous bone marrow cells (C/T). NQO1 also was induced by HQ in wild-type (C/ C) human bone marrow CD34(+) progenitor cells. Our data suggest that failur e to induce functional NQO1 may contribute to the increased risk of benzene poisoning in individuals homozygous for the NQO1 C609T substitution (T/T).