Genetic variants in metabolizing genes NQO1, NQO2, MTHFR and risk of prostate cancer: a study from North India

Mandal, Raju K.; Nissar, Kamran; Mittal, Rama Devi

doi:10.1007/s11033-012-2023-z

Cited by 21 publications

(9 citation statements)

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“…hNQO2 has a common SNP (C659T or L47F) that does not affect enzymic activity but makes hNQO2 more susceptible to proteolysis (Megarity et al , ). hNQO2 SNPs have been linked to prostate cancer (Mandal et al , ), colorectal cancer (Chen et al , ) and prognosis in breast cancer (Hubackova et al , ). hNQO2 has been associated with the activation of chemotherapeutics (Celli et al , ; Jamieson et al , ), and hNQO2 SNPs are associated with the cardiotoxicity of the anthraquinone idarubicin (Megias et al , ).…”

Section: Nitrofuran and Other Nitroaromatic Drug Activation By Azoredmentioning

confidence: 99%

Azoreductases in drug metabolism

Ryan

2016

British J Pharmacology

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Azoreductases are flavoenzymes that have been characterised in a range of prokaryotes and eukaryotes. Bacterial azoreductases are associated with the activation of two classes of drug, azo drugs for the treatment of inflammatory bowel disease and nitrofuran antibiotics. The mechanism of reduction of azo compounds is presented that requires tautomerisation of the azo compound to a quinoneimine and provides a unifying mechanism for the reduction of azo and quinone substrates by azoreductase. The importance of further work in characterisation of azoreductases from enteric bacteria is highlighted to aid in the development of novel drugs for the treatment of colon related disorders.Human azoreductases are known to play a crucial role in the metabolism of a number of quinone containing cancer chemotherapeutic drugs. The mechanism of hydride transfer to quinones, which is shared not only between eukaryotic and prokaryotic azoreductases but the wider family of NAD(P)H quinone oxidoreductases, is outlined. The importance of common SNPs in human azoreductases is described not only in cancer prognosis but also due to their effects on the efficacy of quinone drug based cancer chemotherapeutic regimens. This highlights the need to screen patients for azoreductase SNPs ahead of treatment with these regimens. Non-approved abbreviations5-ASA: 5-aminosalicylate, AcpD: acyl carrier protein phosphodiesterase, ecAzoR: E. coli azoreductase, FAD: flavin adenine dinucleotide, FMN: Flavin mononucleotide, hNQO1/2: human NAD(P)H quinone oxidoreductase 1 and 2, IBD: inflammatory bowel disease, MdaB: Modulator of drug activity B, NAD(P)H: Nicotinamide adenine dinucleotide (phosphate) reduced, NfsB: Nitrofurazone sensitivity protein B, NRH: (Wu et al., 1997) Introduction to azoreductasesAzoreductases are a group of diverse enzymes found in many bacterial and eukaryotic organisms (Fig 1 (Ryan et al., 2014)). The azoreductases discussed in this review are flavin-dependent (typically FMN) enzymes that are able to reductively cleave compounds containing an azo bond. Azo compounds are defined as those that contain an R 1 -N=N-R 2 group, where R 1 and R 2 are typically aromatic groups. Azoreductases are primarily cytosolic enzymes, however they have been shown to be secreted during exposure of bacteria to azo dyes (Morrison et al., 2015). The physiological role of these enzymes in the bacteria remains unclear, however they are constitutively expressed during growth in vitro (Chen et al., 2005;Wang et al., 2007) which suggests a role in homeostasis. The majority of azoreductase research is focused on their use in bioremediation where they can be used for the treatment of waste water contaminated with azo dyes from the textile and cosmetics industries (Singh et al., 2015). This review is unique in focusing on their role in the activation of several classes of drug.To date the majority of studies on azoreductases have been performed on enzymes from aerobic bacteria (Crescente et al., 2016;Nakanishi et al., 2001), in contrast only a single ...

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Section: Nitrofuran and Other Nitroaromatic Drug Activation By Azoredmentioning

confidence: 99%

Azoreductases in drug metabolism

Ryan

2016

British J Pharmacology

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“…Single nucleotide polymorphisms result in the expression of different protein variants of NQO1. The two most prevalent variants in the human population are NQO1*2 (NQO1 609C>T; NQO1 P187S; allelic frequency: 0.22-0.47) and NQO1*3 (NQO1 465C>T; NQO1 R139W; allelic frequency: 0.00-0.05), which are connected to a higher risk for specific cancers [5][6][7][8][9][10][11]. Several studies have focused on NQO1*2 and have shown a reduction or even a loss of the enzymatic activity of NQO1 P187S [12][13][14].…”

mentioning

confidence: 99%

Catalytic competence, structure and stability of the cancer‐associated R139W variant of the human NAD(P)H:quinone oxidoreductase 1 (NQO1)

et al. 2017

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The human NAD(P)H:quinone oxidoreductase 1 (NQO1; EC 1.6.99.2) is an essential enzyme in the antioxidant defence system. Furthermore, NQO1 protects tumour suppressors like p53, p33ING1b and p73 from proteasomal degradation. The activity of NQO1 is also exploited in chemotherapy for the activation of quinone-based treatments. Various single nucleotide polymorphisms are known, such as NQO1*2 and NQO1*3 yielding protein variants of NQO1 with single amino acid replacements, i.e. P187S and R139W, respectively. While the former NOQ1 variant is linked to a higher risk for specific kinds of cancer, the role, if any, of the arginine 139 to tryptophan exchange in disease development remains obscure. On the other hand, mitomycin C-resistant human colon cancer cells were shown to harbour the NQO1*3 variant resulting in substantially reduced enzymatic activity. However, the molecular cause for this decrease remains unclear. In order to resolve this issue, recombinant NQO1 R139W has been characterized biochemically and structurally. In this report, we show by X-ray crystallography and 2D-NMR spectroscopy that this variant adopts the same structure both in the crystal as well as in solution. Furthermore, the kinetic parameters obtained for the variant are similar to those reported for the wild-type protein. Similarly, thermostability of the variant was only slightly affected by the amino acid replacement. Therefore, we conclude that the previously reported effects in human cancer cells cannot be attributed to protein stability or enzyme activity. Instead, it appears that loss of exon 4 during maturation of a large fraction of pre-mRNA is the major reason of the observed lack of enzyme activity and hence reduced activation of quinone-based chemotherapeutics.

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“…Moreover, 2 studies were excluded because they did not provide the exact genotypes and the OR (95%CI) for the association between gene polymorphisms and prostate cancer risk could not be estimated (Zacho et al, 2011;Jackson et al, 2013). As a result, 21 case-control studies were included in our meta-analysis (Kimura et al, 2000;Heijmans et al, 2003;Cicek et al, 2004;Singal et al, 2004;Van Guelpen et al, 2006;Johansson et al, 2007;Reljic et al, 2007;Marchal et al, 2008;Stevens et al, 2008;Collin et al, 2009;Muslumanoglu et al, 2009;Cai et al, 2010;Safarinejad et al, 2010;Wu et al, 2010;Küçükhüseyin et al, 2011;Fard-Esfahani et al, 2012;Kobayashi et al, 2012;Mandal et al, 2012;de Vogel et al, 2013;López-Cortés et al, 2013;Ghasemi et al, 2014).…”

Section: Study Characteristicsmentioning

confidence: 99%

“…This suggests that genetic factors may have different impacts on the risk of prostate cancer in different populations. Several recent studies (Fard-Esfahani et al, 2012;Kobayashi et al, 2012;Mandal et al, 2012;de Vogel et al, 2013;Jackson et al, 2013;López-Cortés et al, 2013;Ghasemi et al, 2014) investigated the association between MTHFR gene polymorphisms and prostate cancer risks, but found conflicting results. Thus, the impact of MTHFR gene polymorphisms (C677T and A1298C) on prostate cancer risk remains unclear.…”

Section: Introductionmentioning

confidence: 99%

Association between MTHFR gene polymorphisms (C677T, A1298C) and genetic susceptibility to prostate cancer: a meta-analysis

Wang

et al. 2015

Genet. Mol. Res.

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ABSTRACT. Genetic polymorphisms (C677T and A1298C) in methylenetetrahydrofolate reductase (MTHFR) were shown to be related to prostate cancer risk in previous studies; however, the results are controversial. We performed a meta-analysis of previous studies and quantitatively estimated these associations. Pubmed, Embase, and Cochrane Library Database were searched for published case-control studies evaluating the association between C677T (or A1298C) and prostate cancer risk. Pooled associations were presented as odds ratios (ORs) along with their 95% confidence intervals. Twenty-one case control studies were identified for meta-analysis that included 21,581 participants. 19191-19202 (2015) No significant associations were found between the MTHFR polymorphisms C677T or A1298C and prostate cancer risk in our meta-analysis. However, in subgroup analyses, the C677T CT polymorphism was associated with increased prostate cancer risk in East Asians (CT vs CC+TT: OR = 1.324, P = 0.03). The A1298C CC polymorphism in MTHFR was also linked to slightly reduced prostate cancer risk in European residents (CC vs AC+AA: OR = 0.751, P = 0.004; CC vs AA: OR = 0.768, P = 0.011), whereas it was associated with a significantly increased prostate cancer risk in Asian residents (CC vs AA: OR = 1.862, P = 0.006). The C677T CT polymorphism of MTHFR may be a risk factor for prostate cancer in East Asians. The association between the MTHFR A1298C CC genotype and prostate cancer risk may vary within different populations. Large-scale well-designed studies are required to confirm these associations.

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Genetic variants in metabolizing genes NQO1, NQO2, MTHFR and risk of prostate cancer: a study from North India

Cited by 21 publications

References 20 publications

Azoreductases in drug metabolism

Azoreductases in drug metabolism

Catalytic competence, structure and stability of the cancer‐associated R139W variant of the human NAD(P)H:quinone oxidoreductase 1 (NQO1)

Association between MTHFR gene polymorphisms (C677T, A1298C) and genetic susceptibility to prostate cancer: a meta-analysis

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