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

Zhou, Hongfei; Kepa, Jadwiga K.; Siegel, David; Miura, Shigenori; Hiraki, Yuji; Ross, David

doi:10.1124/mol.109.057323

Cited by 42 publications

(38 citation statements)

References 35 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Recovery after myelosuppression, which occurs after benzene exposure, has been shown to depend on endothelial cell angiogenesis [38] so we examined HBMEC tube formation after treatment with the benzene metabolite hydroquinone. Hydroquinone treatment of HBMEC led to inhibition of tube formation [49]. Experiments employing gene array analysis indicated that hydroquinone-induced upregulation of chondromodulin 1, an anti angiogenic gene expressed by endothelial cells, was partly responsible for inhibition of tube formation by hydroquinone.…”

Section: Do Benzene Metabolites Affect Endothelial Cell Tube Formamentioning

confidence: 99%

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

Ross¹,

Zhou²,

Siegel³

2011

Chemico-Biological Interactions

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Section: Do Benzene Metabolites Affect Endothelial Cell Tube Formamentioning

confidence: 99%

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

Ross¹,

Zhou²,

Siegel³

2011

Chemico-Biological Interactions

Self Cite

View full text Add to dashboard Cite

show abstract

“…Bone marrow endothelial cells express elevated levels of NQO1 and we have used a transformed human bone marrow endothelial cell line [94] to examine both potential mechanisms of toxicity of benzene metabolites and the protective role of NQO1 [95;96]. Although endothelial cells have relatively high levels of NQO1, they are still susceptible to polyphenolic metabolites of benzene such as hydroquinone albeit at higher concentrations than stromal cells expressing low NQO1 levels.…”

Section: Nqo1 Expression In Bone Marrow Stroma Studies Using Transfomentioning

confidence: 99%

“…Although endothelial cells have relatively high levels of NQO1, they are still susceptible to polyphenolic metabolites of benzene such as hydroquinone albeit at higher concentrations than stromal cells expressing low NQO1 levels. In a recent study we examined gene expression changes in HBMEC cells after treatment with 10 μM hydroquinone [96]. One of these genes, chondromodulin 1 (ChM-I), was upregulated by HQ treatment and we found the inhibitory effects of HQ on endothelial cell tube formation could be partially abrogated by ChM-I knockdown [96].…”

Section: Nqo1 Expression In Bone Marrow Stroma Studies Using Transfomentioning

confidence: 99%

“…In a recent study we examined gene expression changes in HBMEC cells after treatment with 10 μM hydroquinone [96]. One of these genes, chondromodulin 1 (ChM-I), was upregulated by HQ treatment and we found the inhibitory effects of HQ on endothelial cell tube formation could be partially abrogated by ChM-I knockdown [96]. These data suggested a role for ChM-I in the inhibitory effects of HQ on HBMEC and cellular transfection of NQO1 blocked the effects of HQ.…”

Section: Nqo1 Expression In Bone Marrow Stroma Studies Using Transfomentioning

confidence: 99%

See 1 more Smart Citation

Relationships between metabolic and non-metabolic susceptibility factors in benzene toxicity

Ross

Zhou

2010

Chemico-Biological Interactions

Self Cite

View full text Add to dashboard Cite

Reactive metabolites formed from benzene include benzene oxide, trans, trans muconaldehyde, quinones, thiol adducts, phenolic metabolites and oxygen radicals. Susceptibility to the toxic effects of benzene has been suggested to occur partly because of polymorphisms in enzymes involved in benzene metabolism which include cytochrome P450 2E1, epoxide hydrolases, myeloperoxidase, glutathione-S-transferases and quinone reductases. However, susceptibility factors not directly linked to benzene metabolism have also been associated with its toxicity and include p53, proteins involved in DNA repair, genomic stability and expression of cytokines and/or cell adhesion molecules. In this work, we examine potential relationships between metabolic and non-metabolic susceptibility factors using the enzyme NAD(P)H:quinone oxidoreductase (NQO1) as an example. NQO1 may also impact pathways in addition to metabolism of quinones due to protein-protein interactions or other mechanisms related to NQO1 activity. NQO1 has been implicated in stabilizing p53 and in maintaining microtubule integrity. Inhibition or knockdown of NQO1 in bone marrow endothelial cells has been found to lead to deficiencies of E-selectin, ICAM-1 and VCAM-1 adhesion molecule expression after TNFα stimulation. These examples illustrate how the metabolic susceptibility factor NQO1 may influence non-metabolic susceptibility pathways for benzene toxicity. KeywordsBenzene; metabolic susceptibility factors; p53; NQO1; adhesion molecules; bone marrow endothelial cells Metabolic factors in susceptibility to benzene toxicityBenzene induces hematopoietic toxicity and can induce aplastic anemia, myelodysplasia and acute myeloid leukemia after chronic exposure [1;2]. The metabolism of benzene has been investigated extensively and previous reviews have characterized benzene metabolism in a comprehensive manner [3][4][5][6][7]. Consequently, this work is not intended to be a review of benzene metabolism but will focus on metabolic susceptibility factors for benzene toxicity which have been identified in both cell and animal studies and in studies of occupationally-exposed populations. Other susceptibility factors not directly linked to metabolism have also been Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. identified in benzene toxicity and relationships between metabolic and non-metabolic susceptibility factors have not been previously considered. We will therefore discuss potential relationships between these two groups of susceptibility factors using the enzyme NAD(P) H:quinone oxidoreductase 1 (NQO1) as an example and hi...

show abstract

“…TrHBMECs were a generous gift from Dr. Babette B. Weksler (Weill Medical College, Cornell University, Ithaca, NY). Cells were cultured as described previously (Zhou et al, 2009) on 0.2% (w/v) collagen-coated cell culture plates in Dulbecco's modified Eagle's medium (low glucose) supplemented with 5% (v/v) fetal bovine serum, penicillin (100 units/ml), streptomycin (100 units/ml), 3 mM L-glutamine, 10 mM HEPES, and 1% (v/v) BME vitamins (SigmaAldrich). Cells were maintained at 37°C in 5% CO 2 .…”

Section: Methodsmentioning

confidence: 99%

NAD(P)H:quinone Oxidoreductase 1-Compromised Human Bone Marrow Endothelial Cells Exhibit Decreased Adhesion Molecule Expression and CD34⁺Hematopoietic Cell Adhesion

Zhou¹,

Dehn²,

Kepa³

et al. 2010

J Pharmacol Exp Ther

Self Cite

View full text Add to dashboard Cite

NAD(P)H:quinone oxidoreductase 1 (NQO1) deficiency resulting from a homozygous NQO1*2 polymorphism has been associated with an increased risk of benzene-induced myeloid toxicity and a variety of de novo and therapy-induced leukemias. Endothelial cells in human bone marrow form one of the two known hematopoietic stem cell microenvironments and are one of the major cell types that express NQO1 in bone marrow. We have used a transformed human bone marrow endothelial cell (TrHBMEC) line to study the potential impact of a lack of NQO1 activity on adhesion molecule [endothelial leukocyte adhesion molecule 1 (E-selectin), vascular cell adhesion molecule (VCAM)-1, and intercellular adhesion molecule (ICAM)-1] expression and functional adhesion to bone marrow progenitor cells. We used both 5-methoxy-1,2-dimethyl-3-[(4-nitrophenoxy)methyl]indole-4,7-dione (ES936), a mechanism-based inhibitor of NQO1, and anti-NQO1 small interfering RNA to abrogate NQO1 activity. Real-time reverse transcription-polymerase chain reaction data demonstrated a significant inhibition of tumor necrosis factor (TNF)␣-induced E-selectin mRNA levels after ES936 pretreatment. Immunoblot assays demonstrated a significant reduction in TNF␣-stimulated E-selectin, VCAM-1, and ICAM-1 proteins after inhibition or knockdown of NQO1. The mechanisms underlying this effect remain undefined, but modulation of nuclear factor-B (p65), c-Jun, and activating transcription factor 2, transcriptional regulators of adhesion molecules, were observed after inhibition or knockdown of NQO1. Decreased level of E-selectin, VCAM-1, and ICAM-1 also resulted in a functional deficit in adhesion. A parallel plate flow chamber study demonstrated a marked reduction in CD34 ϩ cell (KG1a) adhesion to NQO1-deficient TrHBMECs relative to controls. The reduced adhesive ability of TrHBMECs may affect the function of the vascular stem cell niche and also may contribute to the increased susceptibility of polymorphic individuals lacking NQO1 to leukemias and hematotoxicants such as benzene.

show abstract

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

Cited by 42 publications

References 35 publications

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

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

Relationships between metabolic and non-metabolic susceptibility factors in benzene toxicity

NAD(P)H:quinone Oxidoreductase 1-Compromised Human Bone Marrow Endothelial Cells Exhibit Decreased Adhesion Molecule Expression and CD34⁺Hematopoietic Cell Adhesion

Contact Info

Product

Resources

About

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

Cited by 42 publications

References 35 publications

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

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

Relationships between metabolic and non-metabolic susceptibility factors in benzene toxicity

NAD(P)H:quinone Oxidoreductase 1-Compromised Human Bone Marrow Endothelial Cells Exhibit Decreased Adhesion Molecule Expression and CD34+Hematopoietic Cell Adhesion

Contact Info

Product

Resources

About

NAD(P)H:quinone Oxidoreductase 1-Compromised Human Bone Marrow Endothelial Cells Exhibit Decreased Adhesion Molecule Expression and CD34⁺Hematopoietic Cell Adhesion