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

Abstract

A BSTR ACT 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 (T͞T) have no detectable NQO1. Exposed workers with a T͞T 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 (C͞C) exposed to HQ, whereas no NQO1 was induced by HQ in bone marrow cells with the T͞T genotype. Intermediate induction of NQO1 by HQ was observed in heterozygous bone marrow cells (C͞T). NQO1 also was induced by HQ in wild-type (C͞C) 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 (T͞T).

Association of NQO1 polymorphism with spontaneous breast cancer in two independent populations

“…Hydroquinone, a substrate for detoxification by the NQO enzyme, can induce apoptosis (Moran et al, 1999), which is less stimulated by the 72P variant of p53 (Dumont et al, 2003). How these pathways are actually interwoven remains open for further investigations.…”

Association of genetic polymorphisms in CYP2E1, MPO, NQO1, GSTM1, and GSTT1 genes with benzene poisoning.

“…The C-to-T point variation of this SNP, which causes a proline to serine change, is associated with a loss activity of NQO1 (Traver et al 1992). Moran et al (1999) high-level activity of metabolic enzymes involved in oxidizing benzene to more toxic metabolites such as CYP2E1 and low-level activity of metabolic enzymes participated in detoxification pathway as GSTT1 and GSTM1 were less resistant to benzene toxicity. There was no detectable enzyme activity in the individuals with GSTT1 null genotypes.…”

Benzene Metabolite Hydroquinone Up-Regulates Chondromodulin-I and Inhibits Tube Formation in Human Bone Marrow Endothelial Cells

“…The NQO1*2 polymorphism is a single-nucleotide polymorphism, defined as a C-to-T change at position 609 of the human NQO1 cDNA, corresponding to a proline-to-serine change at position 187 of the protein . The mutant NQO1*2 protein is rapidly degraded by the ubiquitin proteasomal system, resulting in an absence of NQO1 protein in persons carrying the NQO1*2/*2 genotype (Moran et al, 1999). Epidemiological studies have associated the NQO1*2 genotype with an increased risk of benzene-induced myeloid toxicity and a variety of de novo and therapy induced leukemias (Ross, 2005).…”