NQO1, MPO, and the risk of lung cancer: A HuGE review

Abstract

The aim of this study is to summarize the available molecular epidemiologic studies of lung cancer and metabolic genes, such as NAD(P)H quinone reductase 1 (NQO1) and myeloperoxidase (MPO). NQO1 plays a dual role in the detoxification and activation of procarcinogens whereas MPO has Phase I activity by converting lipophilic carcinogens into hydrophilic forms. Variant genotypes of both NQO1 Pro187 Ser and MPO G-463A polymorphisms may be related to low enzyme activity. The Pro/Ser and Ser/Ser genotypes combined of NQO1 was significantly associated with decreased risk of lung cancer in Japanese [random effects odds ratio (OR) ϭ 0.70, 95% confidence interval (CI) ϭ 0.56--0.88] among whom the variant allele is common. The variant genotype of MPO was associated with decreased risk of lung cancer among Caucasians (random effects OR ϭ 0.70, 95% CI ϭ 0.47--1.04). Gene-environment interactions in both polymorphisms may be hampered by inaccurate categorization of tobacco exposure. Evidence on gene-gene interactions is extremely limited. As lung cancer is a multifactorial disease, an improved understanding of such interactions may help identify individuals at risk for developing lung cancer. Such a study should include larger sample size and other polymorphisms in the metabolism of tobaccoderived carcinogens and address interactions with smoking status. The effects of polymorphisms are best represented by their haplotypes. In future studies on lung cancer, the development of haplotype-based approaches will facilitate the evaluation of haplotypic effects, either for selected polymorphisms physically close to each other or for multiple genes within the same drug-metabolism pathway. Genet Med 2005:7(7):463-478.Key Words: lung cancer, NAD(P)H quinone oxidoreductase 1 polymorphism, myeloperoxidase polymorphism, molecular epidemiology, meta-analysis GENES NAD(P)H quinone reductase 1 NAD(P)H quinone oxidoreductase 1 (NQO1, EC 1.6.99.2), formerly referred to as DT-diaphorase, is an important flavoprotein that catalyzes the two-electron reduction of carcinogenic quinoid compounds into their reduced form, such as hydroquinones. 1 Benzo(a)pyrene (BP) is one of the most important carcinogens, and the formation of BP quinone-DNA adduct is prevented by NQO1. 2 In contrast, carcinogenic heterocyclic amines present in smoke are metabolically activated by NQO1. 3 Therefore, this enzyme is thought to be involved in both metabolic activation and detoxification of carcinogens. Higher levels of tissue (cytoplasm) expression of the NQO1 have been detected in the lung, kidney, liver, and skeletal muscle, with lower levels in the heart, brain, and placenta. 4 Myeloperoxidase Myeloperoxidase (MPO, EC 1.11.1.7) is a lysosomal hemoprotein located in the azurophilic granules of polymorphonuclear leukocytes and monocytes. MPO is the most abundant protein in neutrophils, constituting approximately 5% of their dry weight. 5 MPO has Phase I metabolizing activity by converting lipophilic carcinogens into hydrophilic forms. 6 Exposure to a variety of pulmon...

Additional candidates to conventional genes susceptible for lung cancer and changing trend in Japan (Review)

“…Moreover NQO1, NAT2 and several other genes have been reported as new susceptible genes of lung cancer (22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36). The present review focuses on new candidates, then examines all Japanese references by meta-analysis on susceptible genes over the past 20 years, and finally discusses whether new candidates and changing trend in Japan could be caused by environmental change.…”

Updated Meta-analysis of the Association Between CYP2E1 RsaI/PstI Polymorphisms and Lung Cancer Risk in Chinese Population

“…This genetic susceptibility may derive from inherited polymorphisms in genes involved in the metabolism of xenobiotic chemical carcinogens (Shields et al, 2000;Shah et al, 2008). Results from published studies have shown that the variations of drug-metabolizing enzymes including cytochrome P450 (CYP), microsomal epoxide hydrolase 1 (EPHX1), glutathione S-transferase (GST), NAD(P) H quinone oxidoreductase 1 (NQO1), myeloperoxidase (MPO) and arylamine N-acetyltransferases (NATs) were associated with the sensitivity of lung cancer (Kiyohara et al, 2005;Agundez, 2008;Liu et al, 2013;Wang et al, 2013;Zhou et al, 2013).…”

Avaliação citogenética e molecular de trabalhadores intoxicados pelo benzeno

“…Os dois autores sugeriram a utilização destes polimorfismos como marcadores de suscetibilidade individual ao benzeno . (Piedrafita et al, 1996;Williams, 2001;Kiyohara et al, 2005). A frequência do alelo A no gene MPO varia em cada população, tendo sido descrita em 23,4% dos Caucasianos e 14,4% dos asiáticos (Kiyohara et al, 2005).…”

“…(Piedrafita et al, 1996;Williams, 2001;Kiyohara et al, 2005). A frequência do alelo A no gene MPO varia em cada população, tendo sido descrita em 23,4% dos Caucasianos e 14,4% dos asiáticos (Kiyohara et al, 2005). O genótipo variante de MPO 463 G > A tem sido associado ao risco reduzido de se desenvolver leucemia aguda, capacidade que é frequentemente atribuída à ativação diminuída dos carcinógenos por esta variante (Zhang et al, 2007).…”

“…Apesar de não ter sido avaliada na presente investigação, a expressão de genes de reparo do DNA poderia explicar a menor frequência dos alelos desfavoráveis no grupo exposto em comparação com o grupo controle como sugerido em outros estudos da literatura (Kiyohara et al, 2005;Kim et al, 2008).…”