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

Abstract

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 ...

Genetic and Enzymatic Characteristics of CYP2A13 in Relation to Lung Damage

“…In contrast, no association between CYP2A13 polymorphisms and lung cancer was found in the Japanese population [69]. However, the risk of bladder cancer was revealed recently for CYP2A13*1/*2 genotypes in Japanese smokers [70].…”

Cytochrome P450 2A13 3375C>T gene polymorphism in a Turkish population

“…Herr et al (2006) investigated the relationship between CYP2A13 3375C>T polymoprhism and the development of uterine leiomyoma in a case-control study consisting of 126 women with uterine leiomyoma and 243 controls and reported that this polymorphism had a significant association with uterine leiomyoma in a Caucasian population. In another case-control study consisting of 163 patients with bladder cancer and 161 healthy controls, Kumondai et al (2016) examined the association between bladder cancer occurrence and CYP2A13 genetic polymorphisms in Japanese smokers and it was reported that the adjusted odds ratio for the CYP2A13*1/*2 genotype was 0.34 (95% CI=0.17-0.69) and the presence of CYP2A13*2 had a relationship with a decline in the risk of bladder cancer. D' Agostino et al (2008) examined whether the CYP2A13.2 protein has reduced expression levels and/or enzyme activity in the lung in comparison to CY- (Tamaki et al 2011b).…”

Association of CYP2A6 gene deletion with cancers in Japanese elderly: an autopsy study

“…CYP2A6 variants have been studied for tobacco-related cancers such as lung [15,16,17,18,19,20,21], bladder [22,23], esophageal [24], oral [25] and urothelial [26] cancers. Since many cancers are tobacco related, we first studied whether CYP2A6 deletion associate with total cancer in our study sample.…”