Polymorphisms in the NQO1, GSTT and GSTM genes are associated with coronary heart disease and biomarkers of oxidative stress

Martin, Nicholas J.; Collier, Abby C.; Bowen, Lance D.; Pritsos, Karen L.; Goodrich, Geoffrey G.; Arger, Kosta; Cutter, Gary; Pritsos, Chris A.

doi:10.1016/j.mrgentox.2008.09.009

Cited by 58 publications

(32 citation statements)

References 28 publications

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“…Additionally we are able to tease out an apparent "extensive metabolizer" subset of individuals who we know cannot be polymorphic, which probably represents environmental plasticity in NQO1 in this population. Although the effects of NQO1 slow metabolizer polymorphisms/phenotypes have been extensively studied in the context of susceptibility to cancer and effects on drug metabolism, demonstrating environmental mechanisms for enzyme plasticity in human tissues is far more rare (David et al, 2003;Guha et al, 2008;Goodrich et al, 2009;Han et al, 2009;Martin et al, 2009;Vijayakrishnan and Houlston, 2010;Kolesar et al, 2011;Tsvetkov et al, 2011;Li and Zhou, 2014;Lin et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

“…In the adult population, increased cardiovascular and cancer risks (Han et al, 2009;Martin et al, 2009;Kolesar et al, 2011;Lin et al, 2014) as well as increasing severity of Alzheimer's disease in the elderly have also been linked to NQO1 polymorphisms (Tsvetkov et al, 2011). Given these associations with childhood diseases and diseases of aging, the NQO1 enzyme is understudied with respect to ontogeny.…”

Section: Introductionmentioning

confidence: 99%

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The Ontogeny and Population Variability of Human Hepatic NADPH Dehydrogenase Quinone Oxido-Reductase 1 (NQO1)

Rougée

Riches

Berman

et al. 2016

Drug Metabolism and Disposition

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The NADPH dehydrogenase quinone oxido-reductase 1 (NQO1) enzyme is an antioxidant and metabolic enzyme that performs two electron reduction of quinones and other chemicals. Based on the physiologic role(s) of NQO1, we hypothesized that expression and activity of this enzyme would vary with age and other demographic variables. Cytosols from 117 archived human livers were investigated for changes in NQO1 with age, sex, obesity, and ethnicity. Protein expression but not activity of NQO1 was weakly negatively correlated with age (Spearman r = -0.2, P = 0.03). No sex differences were observed for either protein expression or activity and for ethnicity; Caucasians had greater NQO1 activity than Asians (P < 0.05). Overweight children had statistically significantly higher NQO1 activity as compared with ideal weight children (P < 0.05) although this difference was not observed in adults. These findings establish that NQO1 is approximately as active in children as adults. However, modeled NQO1 clearance (both allometric and physiologically based pharmacokinetics) predicted maturation at 23 to 26 years. This is almost certainly an overestimate, with error in the model resulting from a small sample size and inability to scale for age-related changes in hepatic cellularity and/or cytosolic protein content, and indicates a delay in reaching maximum clearance through the NQO1 pathway that is affected by physiologic development as much, or more than, biochemical development. Obesity may increase hepatic NQO1 activity in children, which is likely a protective mechanism in oxidative stress, but may also have significant implications for drug and chemical disposition in obese children.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The Ontogeny and Population Variability of Human Hepatic NADPH Dehydrogenase Quinone Oxido-Reductase 1 (NQO1)

Rougée

Riches

Berman

et al. 2016

Drug Metabolism and Disposition

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“…Of these enzymes, the GST isoforms, in particular, are known to play a significant role in the phase II metabolism of endogenous molecules and administered pharmaceutical agents, whereas NQO1 is primarily responsible for the reduction of oxidative stress-inducing quinones. Increased expression and/or activity of NQO1 has been shown to be an important protective mechanism against oxidative stress in cholestasis (Aleksunes et al, 2006b), coronary heart disease (Martin et al, 2009), acetaminophen-induced hepatotoxicity (Moffit et al, 2007), and primary biliary cirrhosis (Aleksunes et al, 2006a). Although not traditionally considered a drug-metabolizing enzyme, NQO1 is capable of reducing N-acetyl-pbenzoquinone imine, the toxic quinone metabolite of acetaminophen (Moffit et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

Diversity in Antioxidant Response Enzymes in Progressive Stages of Human Nonalcoholic Fatty Liver Disease

et al. 2010

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ABSTRACT:Nonalcoholic fatty liver disease (NAFLD), which occurs in approximately 17 to 40% of Americans, encompasses progressive stages of liver damage ranging from steatosis to nonalcoholic steatohepatitis (NASH). Inflammation and oxidative stress are known characteristics of NAFLD; however, the precise mechanisms occurring during disease progression remain unclear. The purpose of the current study was to determine whether the expression or function of enzymes involved in the antioxidant response, NAD(P)H:quinone oxidoreductase 1 (NQO1), glutathione transferase (GST), and glutamate cysteine ligase, are altered in the progression of human NAFLD. Human livers staged as normal, steatotic, NASH (fatty), and NASH (not fatty) were obtained from the Liver Tissue Cell Distribution System. NQO1 mRNA, protein, and activity tended to increase with disease progression. mRNA levels of the GST isoforms A1, A2, A4, M3, and P1 increased with NAFLD progression. Likewise, GST A and P protein increased with progression; however, GST M protein levels tended to decrease. Of interest, total GST activity toward the substrate 1-chloro-2,4-dinitrobenzene decreased with NAFLD progression. GSH synthesis does not seem to be significantly dysregulated in NAFLD progression; however, the GSH/ oxidized glutathione redox ratio seemed to be reduced with disease severity, indicating the presence of oxidative stress and depletion of GSH throughout progression of NAFLD. Malondialdehyde concentrations were significantly increased with disease progression, further indicating the presence of oxidative stress. Nuclear immunohistochemical staining of nuclear factor E2-related factor 2 (Nrf2), an indicator of activation of the transcription factor, was evident in all stages of NAFLD. The current data suggest that Nrf2 activation occurs in response to disease progression followed by induction of specific Nrf2 targets, whereas functionality of specific antioxidant defense enzymes seems to be impaired as NAFLD progresses.

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“…Another study in patients undergoing standard coronary artery bypass grafting showed a greater inflammatory response, as revealed by increased serum interleukin-6 levels, in the subjects with NQO1*2 genotype as compared with the patients without this polymorphism [34]. Significantly higher levels of C-reactive protein, a biomarker for coronary heart disease, were reported to occur in coronary heart disease patients with lower NQO1 activity [35], indicating a protective role for NQO1 in cardiovascular inflammation. These gene polymorphism studies collectively suggest that NQO1 may have a potentially beneficial activity in protecting against human cardiovascular injury associated with inflammatory stress.…”

Section: Role Of Nqo1 In Human Cardiovascular Diseases and Related Comentioning

confidence: 95%

NAD(P)H:Quinone Oxidoreductase 1 and its Potential Protective Role in Cardiovascular Diseases and Related Conditions

Zhu

2011

Cardiovasc Toxicol

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NAD(P)H: quinone oxidoreductase (NQO) represents a family of flavoproteins that catalyze the two-electron reduction of quinones and their derivatives. In mammalian systems, there are two members of NQO, namely, NQO1 and NQO2. NQO1 utilizes NAD(P)H, whereas NQO2 employs dihydronicotinamide riboside (NRH) as the electron donors. In addition to the well-documented action in reducing quinone compounds and preventing the formation of reactive oxygen species, NQO enzymes, especially NQO1 also possess other important biological activities. These include anti-inflammatory effects, direct scavenging of superoxide anion radicals, and stabilization of p53 and other tumor suppressors. Recently, multiple studies in animal models demonstrated a potential role for NQO1 in protecting against cardiovascular injury and related conditions, including atherogenesis, dyslipidemia, and insulin resistance. Functional gene polymorphisms have been identified in human NQO1 gene. Studies on the association between NQO1 gene polymorphisms and susceptibility to disease development also suggested a possible involvement of NQO1 in human cardiovascular diseases and metabolic syndrome. This review is intended to summarize the recent development regarding the biochemical properties and molecular regulation of NQO1 and its potential beneficial role in cardiovascular diseases and related conditions, including metabolic syndrome.

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Polymorphisms in the NQO1, GSTT and GSTM genes are associated with coronary heart disease and biomarkers of oxidative stress

Cited by 58 publications

References 28 publications

The Ontogeny and Population Variability of Human Hepatic NADPH Dehydrogenase Quinone Oxido-Reductase 1 (NQO1)

The Ontogeny and Population Variability of Human Hepatic NADPH Dehydrogenase Quinone Oxido-Reductase 1 (NQO1)

Diversity in Antioxidant Response Enzymes in Progressive Stages of Human Nonalcoholic Fatty Liver Disease

NAD(P)H:Quinone Oxidoreductase 1 and its Potential Protective Role in Cardiovascular Diseases and Related Conditions

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