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 detoxifies quinones derived from the oxidation of phenolic metabolites of benzene. A polymorphism in NQO1, a C609T substitution, has been identified, and individuals homozygous for this change (T/T) have no detectable NQO1. Exposed workers with a T/T genotype have an increased risk of benzene hematotoxicity. This finding suggests NQO1 is protective against benzene toxicity, which is difficult to reconcile with the lack of detectable NQO1 in human bone marrow. The human promyeloblastic cell line, KG-1a, was used to investigate the ability of the benzene metabolite hydroquinone (HQ) to induce NQO1. A concentration-dependent induction of NQO1 protein and activity was observed in KG-1a cells cultured with HQ. Multiple detoxification systems, including NQO1 and glutathione protect against benzene metabolite-induced toxicity. Indeed, exposure to a noncytotoxic concentration of HQ induced both NQO1 and soluble thiols and protected against HQ-induced apoptosis. NQO1 protein and activity increased in wild-type human bone marrow cells (C/C) exposed to HQ, 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 heterozygous 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 failure to induce functional NQO1 may contribute to the increased risk of benzene poisoning in individuals homozygous for the NQO1 C609T substitution (T/T).
Department of Pharmaceutical Sciences, School of Pharmacy, Campus Box C238, University of Colorado Health Sciences Center, 4200 East Ninth Avenue, Denver, CO 80262, USA.
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JL
Moran
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Siegel
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Ross
D000328:Adult; D019943:Amino Acid Substitution; D018952:Antigens, CD34 / Q000032:analysis; D017209:Apoptosis / Q000187:drug effects; D001554:Benzene / Q000493:pharmacokinetics / Q000633:toxicity*; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D002396:Catechols / Q000494:pharmacology; D004789:Enzyme Activation; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006720:Homozygote; D006801:Humans; D006873:Hydroquinones / Q000494:pharmacology; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000235:genetics*; D011041:Poisoning / Q000235:genetics; D011110:Polymorphism, Genetic; D014407:Tumor Cells, Cultured
D018952:Antigens, CD34; D002396:Catechols; D006873:Hydroquinones; D016660:NAD(P)H Dehydrogenase (Quinone); D001554:Benzene; C034221:catechol; C031927:hydroquinone