Functions and distribution of NQO1 in human bone marrow: potential clues to benzene toxicity.
NADPH:quinone oxidoreductase 1 (NQO1) may perform multiple functions within the cell. It is known to detoxify benzene-derived quinones and generate antioxidant forms of ubiquinone and Vitamin E. Recently suggested roles for NQO1 which may have relevance for mechanisms underlying benzene toxicity include modulation of cellular redox balance, direct scavenging of superoxide, stabilization of p53 and stabilization of microtubules. The NQO1*2 polymorphism is a single nucleotide polymorphism, a C to T change at position 609 of the NQO1 cDNA coding for a proline to serine change at position 187 of the amino acid structure of the protein. The mutant NQO1*2 protein is rapidly degraded by the ubiquitin proteasomal system resulting in a lack of NQO1 protein in individuals carrying the NQO1*2/*2 genotype. The NQO1*2 polymorphism predisposes to benzene toxicity and to various forms of leukemias. NQO1-knockout animals demonstrate myeloid hyperplasia and increased benzene-induced hematotoxicity. NQO1 is not present in freshly isolated human bone marrow hematopoietic cells but can be induced by benzene metabolites. Increases in NQO1 were not observed in NQO1*2/*2 hematopoietic cells, presumably because of the instability of the NQO1*2 protein, suggesting that cells with this genotype would not benefit from any protective effects of NQO1. NQO1 is present in human bone marrow stroma and particularly in endothelial cells. Studies of the functions and distribution of NQO1 in human bone marrow may provide clues to mechanisms underlying benzene toxicity.
Ross
David
D
Department of Pharmaceutical Sciences, School of Pharmacy, University of Colorado Health Sciences Center, Campus Box C238, Denver, CO 80262, USA. David.Ross@uchsc.edu
D000818:Animals; D001554:Benzene / Q000633:toxicity*; D001853:Bone Marrow; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D007938:Leukemia / Q000235:genetics*; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000235:genetics* / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide
D016660:NAD(P)H Dehydrogenase (Quinone); C447479:NQO1 protein, human; D001554:Benzene