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Japanese Journal of Clinical Oncology Advance Access originally published online on August 19, 2008
Japanese Journal of Clinical Oncology 2008 38(9):634-640; doi:10.1093/jjco/hyn081
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© The Author (2008). Published by Oxford University Press. All rights reserved

Possible Relationship Between the Risk of Japanese Bladder Cancer Cases and the CYP4B1 Genotype

Takamitsu Sasaki1, Miho Horikawa2, Kazuhiko Orikasa3, Makoto Sato4, Yoichi Arai3, Yoshitaka Mitachi1, Michinao Mizugaki2, Masaaki Ishikawa1 and Masahiro Hiratsuka1

1 Department of Clinical Pharmacotherapeutics
2 Department of Clinical Pharmaceutics, Tohoku Pharmaceutical University, Sendai
3 Department of Urology, Tohoku University, Sendai
4 Department of Urology, Senen General Hospital, Tagajyo, Miyagi, Japan

For reprints and all correspondence: Masahiro Hiratsuka, Department of Clinical Pharmacotherapeutics, Tohoku Pharmaceutical University, 4-4-1, Komatsushima, Aoba-ku, Sendai 981-8558, Japan. E-mail: mhira{at}tohoku-pharm.ac.jp

Received May 14, 2008; accepted July 17, 2008


   Abstract
TOP
 Abstract
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Funding
 References
 
Cytochrome P450 4B1 (CYP4B1) is involved in the metabolism of several xenobiotics, such as 2-aminofluorene, 2-naphthylamine and benzidine. CYP4B1 allelic variants CYP4B1*1–*7 were recently identified. We thus hypothesized that CYP4B1 genotypes may modify bladder cancer risk. We examined the CYP4B1 genotypes in 169 bladder cancer cases and 190 hospital controls using a hybridization probe assay. Among the CYP4B1 genotypes observed, the most frequent genotypes in both the groups were CYP4B1*1/*1, *1/*2, *1/*3 and *2/*2. Logistic regression analysis revealed that the subjects carrying the CYP4B1*1/*2 or *2/*2 genotypes had a 1.75-fold increased risk of bladder cancer (95% CI=1.03–2.95, P = 0.038) compared with the subjects carrying the CYP4B1*1/*1 genotype. We demonstrated the first genetic study regarding the association of CYP4B1 with bladder cancer. Our results suggest that CYP4B1 genotypes might have an effect on the risk of bladder cancer.

Key Words: CYP4B1 • genotype • bladder cancer


   INTRODUCTION
TOP
 Abstract
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Funding
 References
 
Bladder cancer is the most common malignant cancer of the urinary system. In Japan, epidemiological data indicate that bladder cancer is much more common among males, and the annual mortality rate per 100 000 persons is ~2.6 (1). Environmental exposure to tobacco and occupational carcinogens are the primary risk factors for bladder cancer (2). In particular, the two groups of carcinogens known to initiate bladder cancer are aromatic amines and polycyclic aromatic hydrocarbons (PAHs). These carcinogens are either activated or detoxified by xenobiotic metabolizing enzymes. In general, the metabolism of xenobiotics consists of two phases, Phases I and II. Phase I enzymes, mainly cytochrome P450 (P450s), are typically involved in the metabolic pathways of the activation of carcinogens, whereas Phase II enzymes play a central role in the detoxification (3).

Cytochrome P450 4B1 (CYP4B1) is primarily an extrahepatic form of P450s. CYP4B1 mRNA has been detected in the lungs and bladder in humans (4,5). In animals, CYP4B1 is known to participate in the metabolism of several xenobiotics, such as 2-aminofluorene (2-AF), 2-naphthylamine (2-NA) and benzidine (6,7). Imaoka et al. (5) have reported that the CYP4B1 mRNA expression levels in the bladders of patients with bladder cancer are higher than in those of control subjects without cancer. It has been demonstrated that human bladder microsomes and CYP4B1 expressed in the liver of transgenic mice catalyze the activation of bladder carcinogens such as 2-AF (8). However, it is unclear whether CYP4B1 is involved in the activation or detoxification of bladder carcinogens, and whether it is a risk factor in bladder cancer.

Wide inter-individual differences in the metabolic capacity have been detected in many CYP enzymes. To date, seven variant alleles of CYP4B1 have been identified in French Caucasian and Japanese individuals. We have previously reported that the alleles CYP4B1*2 (AT881–882del, 993G>A, 1018C>T and 1123C>T) and CYP4B1*3 (517C>T) are commonly present in the Japanese population (9). In particular, it has been speculated that a premature termination of protein synthesis by AT881–882del renders the CYP4B1*2 allele non-functional (10). It has been reported that the functional polymorphisms of xenobiotic metabolizing enzyme genes affect the activation and detoxification of carcinogens and, consequently, modify the risk of bladder cancer (11).

Here, we conducted a case–control study to evaluate the potential relationship between the genetic differences of the CYP4B1 gene and the risk of bladder cancer in the Japanese population. We investigated the distribution of CYP4B1 allelic variants and genotypes in a Japanese population with a sample size of 169 bladder cancer cases and 190 hospital controls.


   PATIENTS AND METHODS
TOP
 Abstract
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 Funding
 References
 
Patients
In this case–control study initiated in November 2005, patients with incident bladder cancer were recruited from Tohoku University Hospital, Japan, without age, sex or tumor-stage restrictions. All cases were defined as newly diagnosed and histologically confirmed bladder cancer patients. The control subjects were patients admitted to the same hospital during the same period, with no present or previous history of any cancer. From November 2005 to August 2007, there were 169 incident bladder cancer cases and 190 controls that had been admitted to the hospital during the same period who were eligible and invited to participate in the study. All the participants provided their written informed consents according to the protocols approved by the ethical review board of the Tohoku Pharmaceutical University and the Tohoku University. The cases and controls were interviewed about their smoking habits. The total smoking exposure was calculated as the product of daily tobacco consumption multiplied by the years of smoking. Subjects were divided into ever smokers (≥100 tobaccos) and never smokers (<100 tobaccos) (12,13).

Genetic Analysis
Genomic DNA was isolated from K2-EDTA-anticoagulated peripheral blood using QIAamp DNA Mini Kits (Qiagen, Hilden, Germany) in accordance with the manufacturer's instructions.

The CYP4B1*1 (wild-type), CYP4B1*2 (AT881–882del, 993G>A, 1018C>T and 1123C>T), CYP4B1*3 (517C>T), CYP4B1*5 (993G>A), CYP4B1*6 (517C>T and 1033G>A) and CYP4B1*7 (AT881–882del, 993G>A and 1018C>T) were genotyped by a hybridization probe assay (14). Analysis of the distribution of the five polymorphisms (517C>T, AT881–882del, 993G>A, 1033G>A and 1123C>T) allowed the characterization of six different CYP4B1 alleles (Fig. 1). Sequences for the primers and probes used in this study are listed in Table 1. All the PCR mixtures contained 3 mM MgCl2, 0.5 µM each of the PCR primers, 0.4 µM the LC Red 640-labeled hybridization probes, 0.2 µM fluorescein isothiocianate (FITC)-labeled hybridization probes, 1 µl LightCycler DNA Master Hybridization Mix (Roche Diagnostics Inc., Mannheim, Germany) and 15 ng genomic DNA in a final volume of 10 µl. The fluorometer gain setting was 20 in Channel 2. The cycles consisted of 30 s of initial denaturation at 95°C, followed by 45 cycles at 95°C for 0 s (ramp rate, 20°C/s), 50°C for 5 s (ramp rate 20°C/s) and 72°C for 5 s (ramp rate, 20°C/s). The analytical melting program involved melting the PCR products at 95°C for 30 s and at 40°C for 30 s, followed by increasing the temperature to 80°C at a ramp rate of 0.2°C/s, with continuous fluorescence data collection (Fig. 2).


Figure 1
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  		Figure 1. Allelic variants of CYP4B1 gene identified in this study. Exons containing at least one mutation are illustrated with solid boxes; exons with normal sequence are shown as open boxes.

 

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  		Table 1. Summary of PCR primers and hybridization probes (5'–3')

 

Figure 2
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  		Figure 2. Typical genotyping result for the CYP4B1*2 (AT881–882del) genotype using the LightCycler. In the CYP4B1*2 (AT881–882del) genotyping, curves are plotted for a homozygous sample for the AT deletion variant (AT del/AT del), showing a single peak at 60.0°C; for a homozygous sample for the AT variant (AT/AT), showing a single peak at 67.2°C; and for a heterozygous sample (AT/AT del), showing double peaks at 60.0 and 67.2°C.

 
Statistical Analysis
We evaluated the frequency distributions of demographic variables, including sex, age and smoking status between the case and control subjects using the chi-square test and t-test. The Hardy–Weinberg equilibrium (HWE) was tested separately for the CYP4B1 genotypes in the case and control subjects. The odds ratio (OR) and 95% confidence interval (CI) were used as estimates of the relative risk. The adjusted OR was calculated using unconditional logistic regression to control for age, sex and smoking status. All statistical analyses were performed using Dr SPSS software (SPSS, Chicago, IL, USA).


   RESULTS
TOP
 Abstract
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 Funding
 References
 
The frequency distribution of demographic variables is shown in Table 2. The bladder cancer cases and controls appeared to be adequately matched on sex and age. The mean ages were 68.4 ± 11.0 and 66.3 ± 11.3 years for the cases and controls, respectively (P = 0.070). There were no statistically significant differences between the two groups in terms of sex distribution (79.3% males in cases versus 83.2% males in controls, P = 0.348). As expected, more smokers were present in the bladder cancer patient group as compared with the control group (70.4% ever smokers in cases versus 60.0% ever smokers in controls, P = 0.039). In addition, the duration of smoking among the cancer cases was significantly longer (mean, 23.1 years) than that among the controls (mean, 18.1 years) (P = 0.009). The number of cigarettes smoked (per day) by the cancer patients (mean, 16.9 cigarettes) did not statistically differ compared with that by the controls (mean, 14.9 cigarettes).


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  		Table 2. Frequency distribution of demographic variables for bladder cancer cases and controls

 
Table 3 presents the allele frequencies and genotype distributions of CYP4B1 in bladder cancer cases and controls. The frequencies of CYP4B1*2 (33.1%) and CYP4B1*7 (1.8%) in the cancer cases were higher than those in the controls (27.4 and 0.3%, respectively). On the other hand, the frequency of CYP4B1*3 in the cancer cases (15.4%) was not significantly different from that in the controls (14.5%). Among the CYP4B1 genotypes observed, the most frequent genotypes in both the groups were CYP4B1*1/*1, *1/*2, *1/*3 and *2/*2. The CYP4B1 genotype distributions were in the Hardy–Weinberg equilibrium for both cancer cases (P = 0.910) and controls (P = 0.470). The CYP4B1*1/*2 and *2/*2 frequencies were marginally different between the cancer cases (31.4 and 12.4%, respectively) and controls (26.8 and 8.9%, respectively). When combined with the CYP4B1*1/*2 and *2/*2 genotypes, a trend of increasing bladder cancer risk associated with the CYP4B1 genotypes was apparent among our subjects (OR = 1.77, 95% CI=1.06–2.96, P = 0.029). On the other hand, the CYP4B1*1/*3 and *3/*3 genotypes did not contribute as risk factors in bladder cancer.


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  		Table 3. Allele and genotype frequencies for CYP4B1 in bladder cancer cases and controls and its association with risk of bladder cancer

 
To estimate the risk of bladder cancer in individuals with the common CYP4B1 alleles CYP4B1*2 or *3, the ORs were adjusted for age, sex and smoking status (Table 4). Logistic regression analysis revealed that the subjects carrying the CYP4B1*1/*2 or *2/*2 genotypes had a 1.75-fold increased risk of bladder cancer (95% CI 1.03–2.95, P = 0.038) compared with the subjects carrying the CYP4B1*1/*1 genotype. Furthermore, ever smokers with the CYP4B1*1/*2 or *2/*2 genotype appeared to be at a 2.40-fold higher risk of bladder cancer (95% CI 1.10–5.22, P = 0.026) compared with never smokers having the CYP4B1*1/*1 genotype (Table 5). We also observed an increased risk in bladder cancer associated with the glutathione S-transferase M1 (GSTM1) null genotype in the same cohort (OR = 1.73, 95% CI 1.12–2.68, P = 0.014, data not shown).


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  		Table 4. The adjusted OR for combined CYP4B1 genotypes in bladder cancer cases and controls

 

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  		Table 5. OR for the comprised CYP4B1*2 allele genotypes stratified by smoking status

 

   DISCUSSION
TOP
 Abstract
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
Funding
 References
 
In the present study, we examined the relationship between CYP4B1 genotypes and bladder cancer risk in a Japanese population. Our results demonstrated an increased risk of bladder cancer associated with the CYP4B1*1/*2 or *2/*2 genotypes.

CYP4B1*2 harbors a double nucleotide deletion (AT881–882del) that causes a frameshift leading to the introduction of a premature stop codon. Similar premature terminations of protein synthesis have already been described in other human P450s, and these terminations are responsible for the absence of functional proteins (15,16). The CYP4B1.2 protein, lacking 216 amino acids at the C-terminal sequence, which are known to be essential for heme and substrate binding (17), would be devoid of catalytic activity. CYP4B1 catalyzes the bioactivation of several bladder carcinogens (5–8); therefore, we postulated that CYP4B1 genotypes such as CYP4B1*1/*2 and *2/*2 might be involved in lowering the risk of bladder cancer. However, our investigation revealed that the CYP4B1*1/*2 or *2/*2 genotypes increased the risk of bladder cancer. Furthermore, the risk of bladder cancer was elevated in ever smokers with the CYP4B1*1/*2 or *2/*2 genotypes.

Aune et al. (18) showed that CYP4B1 in rabbit lung microsomes possess the capacity of N- and C-oxidation of the ring carbons of arylamines. Although N-oxidation is an established pathway of carcinogenic activation, ring oxidation is generally regarded as a critical detoxification pathway (19–22). Arylamine ring oxidation generally results in the formation of phenolic derivatives, which are efficiently conjugated and excreted. Thus, CYP4B1 might be partly involved in the detoxification of xenobiotics derived from tobacco, environmental substrates and carcinogenic compounds. CYP1A2 is also known to participate in the metabolism of arylamines (19,21), and several CYP1A2 polymorphic alleles are linked to significantly different activities (23). The CYP1A2 phenotype is categorized into rapid or slow inducibility to environmental toxins and carcinogens. Gago-Dominguez et al. (24) have reported that women with the slow inducibility-type CYP1A2 phenotype who use permanent hair dye have a 2.50-fold increased risk of bladder cancer. Furthermore, Shi et al. (25) have reported that the frequency of CYP2C19 poor metabolizers is significantly lower in bladder cancer cases than in controls. In the carcinogenesis process, CYP enzymes might catalyze not only the activation of procarcinogens but also the detoxification of carcinogens.

Previous studies have shown that in addition to CYP enzymes, the genetic differences in conjugation enzymes affect the risk of bladder cancer (11). In particular, the GSTM1 null genotype was well recognized as a cause of the increased risk of bladder cancer (26,27). Although GSTM1 detoxifies the reactive metabolites of benzo[a]pyrene and other PAHs in tobacco smoke (28), the GSTM1 null genotype is deficient in this enzyme activity (29). When we validated the association between the GSTM1 null phenotype and bladder cancer risk in our subjects, we observed the increased bladder cancer risk associated with the GSTM1 null genotype (data not shown). Similar to the case of the GSTM1 genotype, many studies investigating associations between the N-acetyltransferase 2 (NAT2) genotype and bladder cancer have been reported (11). In a meta-analysis, NAT2 slow acetylators had significant effect on the bladder cancer risk compared with rapid acetylators (27,30). These results suggest that GSTM1 and NAT2 play an important role in the detoxification of bladder carcinogens. In our study, CYP4B1 was considered to catalyze the detoxification of xenobiotics as well as GSTM1 and NAT2. However, previous studies have shown that CYP4B1 participates in the activation of procarcinogens. It is probable that CYP4B1 exerts a modest effect on the metabolic pathways of bladder carcinogens as compared with GSTM1 and NAT2.

Recently, several studies have demonstrated that CYP4B1 plays a potential role in the metabolism of endogenous compounds (31,32). CYP4B1 in rabbit corneal epithelium metabolizes arachidonic acid to 12-hydroxyeicosatrienoic acid (12-HETrE), which exhibit potent inflammatory properties. Its levels in the cornea positively correlate with the in situ inflammatory and neovascular response. Mezentsev et al. (33) have reported that corneal neovascularization is markedly reduced in rabbit eyes receiving subconjunctival injections of CYP4B1-specific small interfering RNAs (siRNA) as compared with control eyes, or eyes receiving the control nonspecific siRNA. CYP4B1 might be involved in the metabolism of endogenous compounds rather than xenobiotics, and the genetic differences might have an impact on certain biological pathways and be associated with pathological processes such as inflammation and carcinogenesis.

We have previously reported the allele frequencies of CYP4B1*1 –*7 among 192 unrelated Japanese subjects (9). The case of allele frequencies in the current study may appear close to the previous control data. However, no statistically significant differences were observed between the control allele frequencies in the current study and the allele frequencies among Japanese subjects in the previous study (data not shown). Moreover, the subjects in previous study comprised both healthy individuals and patients, and were younger (mean age, 52.7 ± 17.5 years) than those in the current study. Matching of age, sex, number of subjects and period of recruitment should be crucial for a case–control study. Although no replication study was presented in an independent sample set, future studies with a large number of samples would be needed to confirm the association of CYP4B1 genotypes and the risk of bladder cancer.

Taken together, this is the first study to demonstrate the relationship between CYP4B1 genetic differences and bladder cancer risk. Further studies are required to confirm whether the functional consequences of the CYP4B1 allele affect the ability of the metabolism of xenobiotics and endogenous compounds in vitro and in vivo.


   Funding
TOP
 Abstract
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Funding
References
 
This work was supported by the High-Tech Research Center Program of the Ministry of Education, Culture, Sports, Science and Technology of Japan and a Grant-in-Aid from the Ministry of Health, Labor and Welfare of Japan.

Conflict of interest statement

None declared.


   References
TOP
 Abstract
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Funding
 References
 
1 National Cancer Center [homepage on the internet]. Japan: Center for Cancer Control and Information Services; c1958–2005. Available at: http://www.ncc.go.jp/jp/index.html Update 2007 Dec 26; cited 2008 May 3.

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24 Gago-Dominguez M, Bell DA, Watson MA, Yuan JM, Castelao JE, Hein DW, et al. Permanent hair dyes and bladder cancer: risk modification by cytochrome P4501A2 and N-acetyltransferases 1 and 2. Carcinogenesis (2003) 24:483–9.[Abstract/Free Full Text]

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27 Garcia-Closas M, Malats N, Silverman D, Dosemeci M, Kogevinas M, Hein DW, et al. NAT2 slow acetylation, GSTM1 null genotype, and risk of bladder cancer: results from the Spanish Bladder Cancer Study and meta-analyses. Lancet (2005) 366:649–59.[CrossRef][Web of Science][Medline]

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