CYP2A6 genetic polymorphism is associated with decreased susceptibility to squamous cell lung cancer in Japanese smokers

Hosono, Hiroki; Kumondai, Masaki; Arai, Tomio; Sugimura, Haruhiko; Sasaki, Takuma; Hirasawa, Noriyasu; Hiratsuka, Masahiro

doi:10.1016/j.dmpk.2015.04.002

Cited by 18 publications

(25 citation statements)

References 30 publications

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“…The genotypes were classified as CYP2A6*1 (ClaI+ To identify the CYP2A6 haplotypes, Sanger sequencing of the CYP2A6 gene for the amplification of all nine exons and exon/intron junctions was performed according to a previously reported method. 25,26,28) We detected the SNP 567C>T of the CYP2A6 gene, which is not registered as a CYP2A6 variant allele in The Human Cytochrome P450 Allele Nomenclature Database, without any other exonic SNPs in the same allele. 29) The genes for subjects that were heterozygous for two SNPs (6558T>C, 6600G>T) were TOPO-cloned to determine the haplotype.…”

Section: Methodsmentioning

confidence: 99%

“…25,26) CYP2A6*4B genotyping was performed based on a previous report with minor modifications. 27) PCR was performed with the genomic DNA samples (>10 ng), 2× AmpliTaq Gold 360 Master Mix (Applied Biosystems, Foster City, CA, U.S.A.), and 0.5 µM each primer (*4B-S, 5′-GCA CAA TAG GGT GAA TGT AGT TAA CA-3′; *4B-AS, 5′-GGA ATA ACT GAA TTT CCT TAA GG-3′).…”

Section: Methodsmentioning

confidence: 99%

“…We recently reported that CYP2A6 genetic polymorphisms were related to the susceptibility of squamous cell lung cancer in Japanese smokers using haplotype-based genotyping methods. 26) Thus, the degree of association between CYP2A6 genetic polymorphisms and the risk of developing cancer may depend on the ethnicity of the population considered.…”

Section: )mentioning

confidence: 99%

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Genetic Polymorphisms of <i>CYP2A6</i> in a Case-Control Study on Bladder Cancer in Japanese Smokers

Kumondai

Hosono

Orikasa

et al. 2016

Biological & Pharmaceutical Bulletin

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Several of the procarcinogens inhaled in tobacco smoke, the primary risk factor for bladder cancer, are activated by CYP2A6. The association between the whole-gene deletion of CYP2A6 (CYP2A6*4) and a reduced risk of bladder cancer was suggested in Chinese Han smokers. However, there is no evidence for association between the risk of bladder cancer and CYP2A6 genotypes in the Japanese population. Using genomic DNA from smokers of the Japanese population (163 bladder cancer patients and 116 controls), we conducted a case-control study to assess the association between CYP2A6 polymorphisms and the risk of bladder cancer. Determination of CYP2A6 genotypes was carried out by amplifying each exon of CYP2A6 using polymerase chain reaction (PCR) and Sanger sequencing. The CYP2A6*4 allele was identified by an allelespecific PCR assay. Bladder cancer risk was evaluated using the activity score (AS) system based on CYP2A6 genotypes. The odds ratios (95% confidence interval) for the AS 0, AS 0.5, AS 1.0, and AS 1.5 groups were 0.46 (0.12-1.83), 0.43 (0.15-1.25), 0.86 (0.40-1.86), and 1.36 (0.60-3.06), respectively. In conclusion, although decreased CYP2A6 AS tended to reduce the risk of bladder cancer in Japanese smokers, no significant association was recognized in this population. However, given the relatively small size of the sample, further study is required to conclude the lack of a statistically significant association between CYP2A6 genotypes and the risk of bladder cancer.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Genetic Polymorphisms of <i>CYP2A6</i> in a Case-Control Study on Bladder Cancer in Japanese Smokers

Kumondai

Hosono

Orikasa

et al. 2016

Biological & Pharmaceutical Bulletin

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“…[6][7][8] CYP2A13 is expressed at higher levels than CYP2A6 in the human bladder and plays a larger role than CYP2A6 in the metabolic activation of NNK in a reconstituted system (intrinsic clearance (CL int ) of CYP2A6 and CYP2A13 was 0.008 and 0.36 µL/ min/nmol CYP, respectively). 5,9) Furthermore, NNK alphahydroxylation by CYP2A13 is higher than that by CYP2A6 in human lung cells.…”

Section: )mentioning

confidence: 99%

“…5) Although the association between CYP2A6 polymorphisms and the risk of developing cancer such as lung and bladder cancer was reported in numerous case-control studies, our recent study revealed no significant association between the development of bladder cancer and CYP2A6 genetic polymorphisms in Japanese smokers. [6][7][8] CYP2A13 is expressed at higher levels than CYP2A6 in the human bladder and plays a larger role than CYP2A6 in the metabolic activation of NNK in a reconstituted system (intrinsic clearance (CL int ) of CYP2A6 and CYP2A13 was 0.008 and 0.36 µL/ min/nmol CYP, respectively). 5,9) Furthermore, NNK alphahydroxylation by CYP2A13 is higher than that by CYP2A6 in human lung cells.…”

mentioning

confidence: 99%

CYP2A13 Genetic Polymorphisms in Relation to the Risk of Bladder Cancer in Japanese Smokers

Kumondai

Hosono

Orikasa

et al. 2016

Biological & Pharmaceutical Bulletin

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Tobacco-specific nitrosamines including 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) andN-nitrosonornicotine (NNN), which can be activated by the metabolic enzyme CYP2A13, are potent procarcinogens. Smoking plays a role in carcinogenesis in the human bladder, which expresses CYP2A13 at a relatively high level. Numerous genetic polymorphisms of CYP2A13 causing amino acid substitution might reduce CYP2A13 metabolic activity toward NNK and NNN, resulting in decreased susceptibility to bladder cancer. The aim of this study was to reveal any association between bladder cancer development and CYP2A13 genetic polymorphisms in Japanese smokers. The CYP2A13 genotype of each subject (163 bladder cancer patients and 161 controls) was determined by next-generation sequencing (NGS) of the full CYP2A13 gene. All samples were genotyped for five CYP2A13 variant alleles (CYP2A13*2, *3, *4, *6, *7). Based on biological logistic regression, the odds ratio (95% confidence interval) for the CYP2A13*1/*2 genotype was 0.34 (0.17-0.69). Thus, CYP2A13 genetic polymorphisms might play important roles in the development of bladder cancer in Japanese smokers.Key words bladder cancer; CYP2A13; smoking; genetic polymorphism; Japanese Human CYP2A6 and CYP2A13 catalyze the metabolism of tobacco-specific nitrosamines such as 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and N-nitrosonornicotine (NNN).1) The carcinogenicity of each compound was previously evaluated by the International Agency for Research on Cancer.2) NNK induces susceptibility to lung tumors in F-344 rats, and detection of tobacco-specific nitrosamines in the urine of smokers indicates that they accumulate in the urinary bladder.3,4) Therefore, NNK and NNN are expected to be activated by metabolic enzymes, such as CYP2A6 and CYP2A13, expressed in the human bladder. 5)Although the association between CYP2A6 polymorphisms and the risk of developing cancer such as lung and bladder cancer was reported in numerous case-control studies, our recent study revealed no significant association between the development of bladder cancer and CYP2A6 genetic polymorphisms in Japanese smokers. [6][7][8] CYP2A13 is expressed at higher levels than CYP2A6 in the human bladder and plays a larger role than CYP2A6 in the metabolic activation of NNK in a reconstituted system (intrinsic clearance (CL int ) of CYP2A6 and CYP2A13 was 0.008 and 0.36 µL/ min/nmol CYP, respectively). 5,9) Furthermore, NNK alphahydroxylation by CYP2A13 is higher than that by CYP2A6 in human lung cells. 10) To date, 10 CYP2A13 allelic variants have been reported (http://www.cypalleles.ki.se/cyp2a13.htm), and most of them affect the metabolism of NNK and NNN. 11)Cancer development caused by local generation of short-lived and carcinogenic metabolites from procarcinogens such as NNK occurs in organs with high expression of CYP2A13. 12)Thus, investigation of the effect of individual differences in CYP2A13 enzymatic activity on the risk of developing cancer would be valuable. However, the role of CYP2A13 in cancer ...

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Biochemical Function of the Respiratory Tract: Metabolism of Xenobiotics

Ding

Winkle³

et al. 2018

Comprehensive Toxicology

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CYP2A6 genetic polymorphism is associated with decreased susceptibility to squamous cell lung cancer in Japanese smokers

Cited by 18 publications

References 30 publications

Genetic Polymorphisms of <i>CYP2A6</i> in a Case-Control Study on Bladder Cancer in Japanese Smokers

Genetic Polymorphisms of <i>CYP2A6</i> in a Case-Control Study on Bladder Cancer in Japanese Smokers

CYP2A13 Genetic Polymorphisms in Relation to the Risk of Bladder Cancer in Japanese Smokers

Biochemical Function of the Respiratory Tract: Metabolism of Xenobiotics

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