Benzene toxicity: The role of the susceptibility factor NQO1 in bone marrow endothelial cell signaling and function

Abstract

The homozygous NQO1*2 polymorphism results in a null NQO1 phenotype and is a susceptibility factor for occupational benzene poisoning. NQO1 plays an important role in detoxification of benzene-derived quinones but plays a role in numerous other non-metabolic cellular functions. NQO1 is expressed in endothelial cells of bone marrow which form the vascular stem cell niche important in stem cell homing and mobilization. We therefore employed a transformed human bone marrow endothelial cell (HBMEC) line to define the effects of compromising NQO1 on endothelial function. Either inhibition or knockdown of NQO1 led to decreased expression of the adhesion molecules E-selectin, VCAM-1 and ICAM-1 and decreased functional adhesion of CD34+ progenitor cells after TNFα stimulation. Suicide inhibition or knockdown of NQO1 decreased NFκB p105 precursor and NFκB p50 subunit levels as well as leading to decreased nuclear levels of NFκB phospho-p65. An additional function of endothelial cells is tube formation and angiogenesis which was inhibited by the benzene metabolite hydroquinone suggesting that endothelial function may be affected at multiple levels after exposure of NQO1*2 polymorphic individuals to benzene. These data demonstrate that NQO1 plays an upstream role in NFκB signaling and adhesion molecule expression in HBMEC and that NQO1 has important regulatory effects in its own right in addition to being a marker for Nrf-2 activation. Metabolic susceptibility factors such as NQO1 have roles in addition to detoxification of reactive intermediates and interrogation of these novel roles can inform both mechanisms of toxicity and human risk assessment.

Human NAD(P)H:quinone Oxidoreductase 1 (NQO1)-Mediated Inactivation of Reactive Quinoneimine Metabolites of Diclofenac and Mefenamic Acid

“…Furthermore, heterozygous NQO1*1/*2 will likely have a lower NQO1 expression level compared to that of NQO1*1/*1 . The NQO1*2 polymorphism has been associated with an increased risk to benzene toxicity and increased susceptibility to cancer. , The effect of the NQO1*3 polymorphism on the phenotype is not extensively studied. Although comparable in stability to the wild type, changes in activity were shown, most notably a decreased activity for mitomycin C .…”

“…6 The NQO1*2 polymorphism has been associated with an increased risk to benzene toxicity and increased susceptibility to cancer. 7,8 The effect of the NQO1*3 polymorphism on the phenotype is not extensively studied. Although comparable in stability to the wild type, changes in activity were shown, most notably a decreased activity for mitomycin C. 9 The allele frequency of NQO1*3 is much lower, the highest frequency (0.05) being reported in Caucasians.…”

Genetic, epigenetic, and lineage-directed mechanisms in benzene-induced malignancies and hematotoxicity targeting hematopoietic stem cells niche

“…20 In the context of benzene toxicity targeting bone marrow, NAD(P)H:quinone oxidoreductase 1 (NQO1), which is produced by bone marrow stromal cell, protects against benzene toxicity by catalyzing the obligatory two-electron reduction of 1,4-BQ into HQ. [21][22][23] Thus, NQO1 plays an important role in 1,4-BQ detoxification and cellular protection against oxidative stress following BQ exposure. 24 Overall, the risk of toxicity following benzene exposure targeting the hematopoietic system can be determined by the activity of metabolic enzymes involved in benzene activation and detoxification.…”

Efeitos da exposição in vivo à hidroquinona sobre funções do tecido traqueal e de macrófagos alveolares de camundongos

“…In this condition, HQ exposure did not alter the number of circulating MN cells but reduced MN cells into the BALF after LPS inhalation. Leukocyte migration to the inflammatory site depends on highly controlled sequential expression of adhesion molecules and inflammatory mediators and it has been described that in vivo HQ exposure caused impairment on neutrophil migration due to altered adhesion molecules expression on cell membranes Ross et al, 2010;Ribeiro et al, 2011 -submitted).…”