CYP2A6 Gene Deletion Reduces Susceptibility to Lung Cancer

Miyamoto, Michiyuki; Umetsu, Yuri; Dosaka‐Akita, Hirotoshi; Sawamura, Yuichi; Yokota, Jun; Kunitoh, Hideo; Nemoto, Nobuo; Sato, Kunio; Ariyoshi, Noritaka; Kamataki, Tetsuya

doi:10.1006/bbrc.1999.1089

Cited by 143 publications

(107 citation statements)

References 8 publications

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“…The results of our case control studies with over 3,400 Japanese subjects clearly supported our idea that subjects homozygous for the CYP2A6*4C (4-5z of Japanese subjects) have considerably lower risk of lung cancer (32). This tendency was seen in smokers but not in non-smokers (33), lending a support to our idea.…”

Section: Large Scale Epidemiological Study On the Association Of Genesupporting

confidence: 88%

Genetic Polymorphism of CYP2A6 and Tobacco-Related Cancer Risk: From the Establishment of Genetically Engineered Salmonella to Large Scale Epidemiology

Kamataki

2006

Genes and Environment

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Most mutagens/carcinogens are metabolically activated by enzymes such as cytochrome P450 to exert their mutagenicity or carcinogenicity. Since the catalytic properties of cytochrome P450 vary among animal species, it was necessary to establish a mutation-detection system carrying human cytochrome P450 to estimate if the chemicals are mutagenic in humans. For this purpose, we introduced genes for human cytochrome P450 together with NADPH-cytochrome P450 reductase to establish humanized Salmonella typhimurium. Using the genetically engineered Salmonella typhimurium, we found that CYP2A6 was involved in the metabolic activation of a variety of nitrosamines such as 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) contained in tobacco smoke. Analyzing the CYP2A6 gene of subjects who showed a poor metabolic phenotype towards (＋)-cis-3,5-dimethyl-2-(3-pyridyl)thiazoline-4-one hydrochloride (SM-12502), we discovered a novel mutant allele (CYP2A6*4C) lacking the whole CYP2A6 gene. Taking these results into account, we hypothesized that the subjects carrying the CYP2A6*4C allele had lower risk to tobacco-related lung cancer. In accordance with our hypothesis, our large scale epidemiological studies clearly indicated that smokers homozygous for the CYP2A6*4C allele showed much smaller odds ratios towards cancer risk. Other mutant alleles reducing the CYP2A6 activity besides the CYP2A6*4C allele also reduced the risk for lung cancer in smokers, particularly squamous cell carcinoma and small cell carcinoma frequently seen in smokers. 8-Methoxypsoralen, an inhibitor of CYP2A6, e‹ciently prevented the occurrence of adenoma caused by NNK in A/J mice.

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Section: Large Scale Epidemiological Study On the Association Of Genesupporting

confidence: 88%

Genetic Polymorphism of CYP2A6 and Tobacco-Related Cancer Risk: From the Establishment of Genetically Engineered Salmonella to Large Scale Epidemiology

Kamataki

2006

Genes and Environment

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“…It is reported that Japanese immigrants to Hawaii have lower relative risk of lung cancer associated with cigarette smoking than those of other ethnic origins. 47 Some of the germline polymorphism in drug-metabolizing enzymes, such as CYP2A6, 48 are reported to be associated with a reduced risk of lung cancer associated with cigarette smoking in the Japanese population and a combination of these polymorphism may cause the difference in susceptibility between countries.…”

Section: Discussionmentioning

confidence: 99%

Cigarette smoking and subsequent risk of lung cancer by histologic type in middle‐aged Japanese men and women: The JPHC study

Sobue

Yamamoto

Hara

et al. 2002

Intl Journal of Cancer

142

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In order to update the findings of relative risk associated with cigarette smoking for lung cancer by histologic type in Japan, the data from a population-based cohort study of 91,738 men and women were analyzed. During 1990 -1999, 422 lung cancer incident cases were identified. The relative risk for all incident cases associated with current smokers versus non-smokers was 4.5 [95% confidence interval (CI): 3.0 -6.8] and 4.2 (95% CI: 2.4 -7.2), for men and women, respectively. When divided by histologic type, relative risk for squamous cell carcinoma and small cell carcinoma was 12.7 (95% CI: 4.7-34.7) and 17.5 (95% CI: 4.9 -62.1), while for adenocarcinoma it was 2.8 (95% CI: 1.6 -4.9) and 2.0 (95% CI: 0.8 -5.0) for men and women, respectively. We confirmed that the lung cancer risk in men rose with increasing cigarette smoking, especially the duration of smoking among current smokers and decreased after the cessation of smoking among former smokers. Unlike the US or European countries, the relative risk did not increase in this updated study, compared with previous studies in 1960s to 1990s in Japan either for all incident cases or for specific histologic types and the magnitude of relative risks was substantially lower than that observed in the US or European countries, especially for adenocarcinoma. © 2002 Wiley-Liss, Inc. Key words: lung cancer; histologic type; cigarette smoking; relative riskRecent trends in lung cancer incidence showed a relative increase in adenocarcinoma as compared with squamous cell carcinoma for both men and women in various countries. [1][2][3][4][5][6] It is hypothesized that this trend is mainly due to the dissemination of low-tar filter cigarettes, 7-9 since filters mainly remove the larger particles in cigarette smoke, which tend to be deposited in the central large bronchus where most squamous cell carcinomas arise. However, such filters do not remove smaller particles, which tend to reach the peripheral region of the lung where adenocarcinomas arise. Moreover, in order to compensate for nicotine intake, smokers of low-tar filter cigarettes tend to inhale more deeply than those of nonfilter cigarettes, which results in more cigarette smoke reaching the peripheral region. Switching from nonfilter to filter cigarettes occurred mostly during in the US, the UK and Japan, where market share of filtered cigarette exceeded that of nonfilter cigarette in 1959, 1967 and 1965, respectively. 10,11 In the US and European countries, this hypothesis is supported by the finding that the magnitude of the relative risk of lung adenocarcinoma associated with cigarette smoking increased in recent studies, just when the usage of low-tar filter cigarette became more widespread among study subjects. It is reported from the US that the risk of lung adenocarcinoma is many times higher for current smokers than non-smokers, i.e., 19.0-fold for men and 8.1-fold for women in the Cancer Prevention Study (CPS) II (1982II ( -1984, while in CPS I (1959 -1961) corresponding estimates were 4.6 and 1.5 for me...

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“…London et al 12 and Loriot et al 13 reported no association between CYP2A6 variants and lung cancer. Miyamoto et al 14 reported significant association of CYP2A6 homozygote deletion with decreased lung cancer risk in Japanese populations (OR ϭ 0.25, 95% CI 0.08 -0.83). Kamataki et al 11 reported a significantly lower frequency of CYP2A6 gene whole deletion in lung cancer patients compared to healthy volunteers.…”

Section: Discussionmentioning

confidence: 99%

“…8,10 Several recent reports have investigated the role of CYP2A6 genetic polymorphisms in tobacco dependence and lung cancer risk, with conflicting results. [11][12][13][14][15] Less is known, however, about the role of CYP2A6 polymorphic enzymes in gastric cancer. There are few reports on CYP2E1 RsaI polymorphisms and gastric cancer.…”

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confidence: 99%

Effects of cytochrome P450 (CYP) 2A6 gene deletion and CYP2E1 genotypes on gastric adenocarcinoma

Tsukino

Kuroda

Qiu

et al. 2002

Intl Journal of Cancer

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Cytochrome P450 (CYP) 2A6 and CYP2E1 are enzymes with a high ability to activate a nitrosamine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), to its potent and ultimate carcinogens. The polymorphic CYP2A6 and CYP2E1 have been implicated in increased susceptibility to certain malignancies. In our study, 120 Japanese patients with gastric adenocarcinoma and 158 healthy controls were compared for frequencies of CYP2A6 and CYP2E1 genotypes. The frequency with which the subjects carried homozygotes of the CYP2A6 gene deletion allele, which causes lack of the enzyme activity, was significantly higher in the gastric cancer patients than in the healthy control subjects (OR ‫؍‬ 3.14, 95% confidence interval (95% CI) ‫؍‬ 1.05-9.41). Subdividing gastric adenocarcinoma according to tumor differentiation, patients with the well-differentiated type were 4. Although gastric cancer incidence has fallen markedly over the past 50 years in industrialized nations, it remains the second leading cause of cancer death in Japan. Epidemiological and experimental evidence have indicated that excess salt intake, which promotes cell replication, increases gastric cancer risk. 1,2 There is considerable evidence to support the view that carcinogenic N-nitrosamine derivatives are important factors in human cancer, including gastric cancer. The chemical mechanisms of carcinogenesis by these nitrosamines in humans are therefore of considerable interest. 3,4 Numerous studies have shown that several cytochrome P450 (CYP) enzymes, particularly cytochrome P4502A6 (CYP2A6) and cytochrome P4502E1 (CYP2E1), catalyze metabolic activation of nitrosamine derivatives, including N-nitroso-dialkyiamines and tobacco-smoke-related nitrosamine. [5][6][7][8] Genetic polymorphisms for CYP2A6 have been described and 2 variant alleles associated with reduced activity have been identified. Variant 1 (CYP2A6*2) and Variant 2 (CYP2A6*3) are the results of amino acid exchanged for wildtype (CYP2A6*1). Recently, Kitagawa et al. 9 revealed that a novel deletion genotype variant of the CYP2A6 gene was one of the major polymorphic genes in Japanese lacking CYP2A6 activity.In addition, CYP2E1 represents a major CYP isoform in the human liver and is also expressed in extrahepatic tissue. This enzyme can be induced by certain chemicals, such as ethanol and large interindividual variations have been observed, suggesting that the variation may be due to genetic polymorphism. It was reported that RsaI polymorphism, which is located in the 5Ј-flanking region of CYP2E1 gene, has been shown to be associated with the transcriptional regulation of gene expression, resulting in different expression levels of the CYP2E1 mRNA. 6 CYP2E1 participated in the metabolic activation of various N-nitrosamines, including a potent tobacco-specific carcinogen, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone. 8,10 Several recent reports have investigated the role of CYP2A6 genetic polymorphisms in tobacco dependence and lung cancer risk, with conflicting results. [11][12][13][14][15] Less ...

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CYP2A6 Gene Deletion Reduces Susceptibility to Lung Cancer

Cited by 143 publications

References 8 publications

Genetic Polymorphism of CYP2A6 and Tobacco-Related Cancer Risk: From the Establishment of Genetically Engineered Salmonella to Large Scale Epidemiology

Genetic Polymorphism of CYP2A6 and Tobacco-Related Cancer Risk: From the Establishment of Genetically Engineered Salmonella to Large Scale Epidemiology

Cigarette smoking and subsequent risk of lung cancer by histologic type in middle‐aged Japanese men and women: The JPHC study

Effects of cytochrome P450 (CYP) 2A6 gene deletion and CYP2E1 genotypes on gastric adenocarcinoma

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