Identification of an NAD(P)H:quinone oxidoreductase polymorphism and its association with lung cancer and smoking

Rosvold, Elizabeth; McGlynn, Katherine A.; Lustbader, Edward D.; Buetow, Kenneth H.

doi:10.1097/00008571-199508000-00003

Cited by 111 publications

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“…Individuals carrying both mutated genomic alleles are completely lacking in NQO1 activity, whereas heterozygous individuals with one mutated allele have low-to-intermediate NQO1 activity as compared with wild-type individuals (12). Approximately 2-4% human individuals are homozygous and 20 -25% are heterozygous for this mutation (13)(14)(15)(16).…”

mentioning

confidence: 99%

NQO1 and NQO2 Regulation of Humoral Immunity and Autoimmunity

Iskander

Han

et al. 2006

Journal of Biological Chemistry

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NAD(P)H:quinone oxidoreductase 1 (NQO1) and NRH:quinone oxidoreductase 2 (NQO2) are cytosolic enzymes that catalyze metabolic reduction of quinones and derivatives. NQO1-null and NQO2-null mice were generated that showed decreased lymphocytes in peripheral blood, myeloid hyperplasia, and increased sensitivity to skin carcinogenesis. In this report, we investigated the in vivo role of NQO1 and NQO2 in immune response and autoimmunity. Both NQO1-null and NQO2-null mice showed decreased B-cells in blood, lower germinal center response, altered B cell homing, and impaired primary and secondary immune responses. NQO1-null and NQO2-null mice also showed susceptibility to autoimmune disease as revealed by decreased apoptosis in thymocytes and predisposition to collagen-induced arthritis. Further experiments showed accumulation of NADH and NRH, cofactors for NQO1 and NQO2, indicating altered intracellular redox status. The studies also demonstrated decreased expression and lack of activation of immune-related factor NF-B. Microarray analysis showed altered chemokines and chemokine receptors. These results suggest that the loss of NQO1 and NQO2 leads to altered intracellular redox status, decreased expression and activation of NF-B, and altered chemokines. The results led to the conclusion that NQO1 and NQO2 are endogenous factors in the regulation of immune response and autoimmunity.Quinone oxidoreductases (NQO1 and NQO2) 2 are cytosolic flavoproteins that catalyze two-electron metabolic reduction and detoxification of quinones and derivatives (1, 2). This leads to protection of cells against oxidative stress and neoplasia. However, in some cases, especially in the absence of conjugating reactions, the hydroquinones undergo oxidation to generate reactive oxygen species causing damage to cells (1, 2). NQO1-null and NQO2-null mice lacking respective gene expression showed alterations in intracellular redox status, myeloid hyperplasia, and higher susceptibility to skin carcinogenesis (3-7). Both NQO1-null and NQO2-null mice demonstrated lower expression and induction of tumor suppressor p53 (7,8). NQO1 protects p53 from ubiquitin-independent 20 S proteasomal degradation (9).A cytosine to thymidine (C 3 T) polymorphism in exon 6 of human NQO1 gene produces a proline to serine (P187S) substitution that destabilizes the protein (10, 11). Individuals carrying both mutated genomic alleles are completely lacking in NQO1 activity, whereas heterozygous individuals with one mutated allele have low-to-intermediate NQO1 activity as compared with wild-type individuals (12). Approximately 2-4% human individuals are homozygous and 20 -25% are heterozygous for this mutation (13-16).The roles of genetic factors in immune deficiency and autoimmune diseases have been recognized for decades (17). B cells play a key role in regulation of immune system. B cells produce antibodies, provide support to other mononuclear cells, and contribute directly to inflammatory pathways (18). Impaired B cell production, maturation, homing, and activation are...

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confidence: 99%

NQO1 and NQO2 Regulation of Humoral Immunity and Autoimmunity

Iskander

Han

et al. 2006

Journal of Biological Chemistry

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“…Numerous studies have correlated altered susceptibility to a number of diseases, the existence of particular alleles and the expression of certain phase 1 and/or phase 2 drug metabolizing enzymes (e.g., Rosvold et al, 1995;Taioli et al, 1998;Ford et al, 2000;Wu et al, 2001). In the case of CYP, the wide interindividual variation in expression is due to both genetic and environmental factors.…”

Section: Association Of Flavin-containing Monooxygenase With Human DImentioning

confidence: 99%

Mammalian flavin-containing monooxygenases: structure/function, genetic polymorphisms and role in drug metabolism

Krueger

Williams

2005

Pharmacology & Therapeutics

493

444

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Flavin-containing monooxygenase (FMO) oxygenates drugs and xenobiotics containing a "softnucleophile", usually nitrogen or sulfur. FMO, like cytochrome P450 (CYP), is a monooxygenase, utilizing the reducing equivalents of NADPH to reduce 1 atom of molecular oxygen to water, while the other atom is used to oxidize the substrate. FMO and CYP also exhibit similar tissue and cellular location, molecular weight, substrate specificity, and exist as multiple enzymes under developmental control. The human FMO functional gene family is much smaller (5 families each with a single member) than CYP. FMO does not require a reductase to transfer electrons from NADPH and the catalytic cycle of the 2 monooxygenases is strikingly different. Another distinction is the lack of induction of FMOs by xenobiotics.In general, CYP is the major contributor to oxidative xenobiotic metabolism. However, FMO activity may be of significance in a number of cases and should not be overlooked. FMO and CYP have overlapping substrate specificities, but often yield distinct metabolites with potentially significant toxicological/pharmacological consequences.The physiological function(s) of FMO are poorly understood. Three of the 5 expressed human FMO genes, FMO1, FMO2 and FMO3, exhibit genetic polymorphisms. The most studied of these is FMO3 (adult human liver) in which mutant alleles contribute to the disease known as trimethylaminuria. The consequences of these FMO genetic polymorphisms in drug metabolism and human health are areas of research requiring further exploration.

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“…Hence, differences in the quality and quantity of NQO enzymes are likely to have a significant influence on the susceptibility to various common diseases, including arteriosclerosis, hypertension, and diabetes mellitus, as well as cancer. In fact, a Pro203Ser amino-acid substitution in the NQO1 gene has been implicated as a factor influencing risk for lung cancer (Rosvold et al 1995;Chen et al 1999;Lin et al 1999), cutaneous basal cell carcinoma (Clairmont et al 1999), and urological malignancy (Schulz et al 1997). In addition, this change appears to be associated with risk for a subtype of colon cancer characterized by mutation at codon 12 of the K-ras gene (Lafuente et al 2000).…”

Section: Quinone Oxidoreductasesmentioning

confidence: 99%

Catalog of 320 single nucleotide polymorphisms (SNPs) in 20 quinone oxidoreductase and sulfotransferase genes

et al. 2001

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Single nucleotide polymorphisms (SNPs) in genes encoding drug-metabolizing enzymes, transporters, receptors, and other drug targets have been widely implicated as contributors to differences among individuals as regards the efficacy and toxicity of many medications, as well as the susceptibility to complex diseases. By combining the polymerase chain reaction (PCR) technique with direct sequencing, we screened genomic DNAs from 48 Japanese volunteers for SNPs in genes encoding three quinone oxidoreductases (NQO1, NQO2, and PIG3) and 17 sulfotransferases (SULT1A1, SULT1A2, SULT1A3, SULT1C1, SULT1C2, SULT2A1, SULT2B1, ST1B2, TPST1, TPST2, SULTX3, STE, CST, CHST2, CHST4, and CHST5). In all, we identified 320 SNPs from these 20 loci: 22 within coding elements, 21 in 5Ј flanking regions, 10 in 5Ј untranslated regions, 223 in introns, 19 in 3Ј untranslated regions, and 25 in 3Ј flanking regions. The ratio of transitions to transversions was approximately 2.3 to 1. Of the 22 coding SNPs, 6 were nonsynonymous substitutions that resulted in amino-acid substitutions. The highdensity SNP maps we constructed from this data for each of the quinone oxidoreductases and sulfotransferases examined here should provide useful information for investigations designed to detect association(s) between genetic variations and common diseases or responsiveness to drug therapy.

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Identification of an NAD(P)H:quinone oxidoreductase polymorphism and its association with lung cancer and smoking

Cited by 111 publications

References 0 publications

NQO1 and NQO2 Regulation of Humoral Immunity and Autoimmunity

NQO1 and NQO2 Regulation of Humoral Immunity and Autoimmunity

Mammalian flavin-containing monooxygenases: structure/function, genetic polymorphisms and role in drug metabolism

Catalog of 320 single nucleotide polymorphisms (SNPs) in 20 quinone oxidoreductase and sulfotransferase genes

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