Effects of occupation, lifestyle and genetic polymorphisms of CYP1A1, CYP2E1, GSTM1 and GSTT1 on urinary 1-hydroxypyrene and 2-naphthol concentrations
Hong-Mei Nan,
Heon Kim,4,
Hyun-Sul Lim,1,
Jung Keun Choi,2,
Toshihiro Kawamoto,3,
Jong-Won Kang,
Chul-Ho Lee,
Yong-Dae Kim and
Eun Hye Kwon,2
Department of Preventive Medicine, College of Medicine, Chungbuk National University, 48 San Kaeshin-dong, Hungdok-gu, Cheongju, Chungbuk 361-763, South Korea,
1 Department of Preventive Medicine, College of Medicine, Dongguk University, Kyungju, South Korea,
2 Center for Occupational Epidemiology and Surveillance, Industrial Safety and Health Research Institute, Korea Occupational Safety and Health Agency, Changwon, South Korea
3 Department of Environmental Health, University of Occupational and Environmental Health, Kitakyushu, Japan
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Abstract
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This study was undertaken to determine the effects of occupation, lifestyle and the genetic polymorphisms of cytochrome P450 1A1 (CYP1A1), cytochrome P450 2E1 (CYP2E1) and glutathione S-transferases µ1 (GSTM1) and
1 (GSTT1) on the concentrations of urinary 1-hydroxypyrene (1-OHP) and 2-naphthol among Korean coke oven workers and university students. The study subjects included 90 coke oven workers and 128 university students. A questionnaire was used to obtain detailed data about the work area, smoking habits and food intake of subjects. Associations between urinary polycyclic aromatic hydrocarbon (PAH) concentrations and occupation, smoking status, total airborne PAH level and genetic polymorphisms were tested. Urinary 1-OHP and 2-naphthol concentrations were higher in coke oven workers than in students and correlated significantly with work area. Urinary 2-naphthol concentrations increased with an increase in the level of cigarette smoking in students. Total airborne PAH level correlated with urinary 1-OHP concentration in coke oven workers. Urinary 1-OHP and 2-naphthol concentrations were higher in coke oven workers with the c1/c2 or c2/c2 genotype of CYP2E1 than in those with the c1/c1 genotype. Urinary 2-naphthol concentrations were higher in GSTM1-null workers than in GSTM1-positive workers. In multiple regression analysis CYP2E1 was a significant factor determining urinary 1-OHP concentrations in coke oven workers. CYP2E1 and GSTM1 were significant determinants for urinary 2-naphthol concentrations in coke oven workers and GSTM1 and smoking were prognosticators among university students. Urinary 1-OHP is a better indicator of occupational exposure to PAH in coke oven workers than 2-naphthol, whereas urinary 2-naphthol may be more sensitive for non-occupational inhalation exposure to PAH. In occupationally exposed populations CYP2E1 and GSTM1 appear to play an important role in the metabolism of pyrene and naphthalene. In individuals not occupationally exposed to PAHs GSTM1 and smoking seem to influence the urinary concentration of 2-naphthol.
Abbreviations: CYP, cytochromes P-450; GST, glutathione S-transferase; 1-OHP, 1-hydroxypyrene; PAH, polycyclic aromatic hydrocarbon; TSP, total suspended particulate.
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Introduction
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Polycyclic aromatic hydrocarbons (PAHs) are formed during the incomplete combustion of fossil fuels and are widely distributed in the environment (1). Epidemiological studies have shown an increased incidence of cancer among workers exposed to PAHs (2). Human exposure to PAHs may occur through smoking, occupational factors, polluted air, food consumption (3) and in medications (4).
Urinary 1-hydroxypyrene (1-OHP) is the major metabolite of pyrene and its concentration has been used as a biomarker of PAH exposure since Jongeneelen et al. (5) developed a method for measuring urinary 1-OHP using high performance liquid chromatography. In many previous studies urinary 1-OHP has been used as a biological marker for exposure to PAH in coke oven workers (68). Naphthalene is a dicyclic aromatic hydrocarbon and a predominant compound in various types of occupational exposure (9). Absorbed naphthalene undergoes rapid hydroxylation to 1- and 2-naphthol and these conjugate to form more water-soluble derivatives, which are excreted in urine (10,11). Recently, a sensitive liquid chromatographic method for the quantification of 2-naphthol in human urine has been reported (12).
Cytochromes P-450 (CYP) are biotransformation phase I enzymes which catalyze the metabolism of xenobiotics, including PAHs, in human cells. Cytochromes P-450 1A1 (CYP1A1) and 2E1 (CYP2E1) catalyze the oxidation of pyrene and naphthalene and the formation of their active oxygen metabolites (1315). Glutathione S-transferases (GSTs) are biotransformation phase II enzymes, which have been reported to catalyze the conjugation of PAH diol epoxide metabolites with reduced glutathione. Because they are important detoxification enzymes, GSTs may play a major role in protecting the individual from PAH-induced mutagenesis and carcinogenesis (16,17).
In the present study we have evaluated the effects of the lifestyle of subjects, including smoking and dietary habits, and genetic polymorphisms of CYP1A1, CYP2E1 and GSTs µ1 (GSTM1) and
1 (GSTT1) on concentrations of urinary 1-OHP and 2-naphthol separately in coke oven workers and in university students without occupational exposure to PAHs.
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Materials and methods
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Study subjects
The subjects of this study were 90 male Korean coke oven workers and 128 Korean university students (81 male and 47 female) without occupational exposure to PAHs. All subjects gave their informed consent. A questionnaire was used to establish gross aspects of lifestyle, i.e. age, smoking habits, occupation and dietary habits. The work areas of coke oven workers were classified into `top', `side', `bottom', `cleaning' and `superintendent' (18). Spot urine specimens and blood samples were collected from the subjects and kept at 20°C until analyzed.
Analysis of airborne PAHs
Airborne PAHs were sampled and analyzed with NIOSH method no. 5515 (19). For sampling of air in the working environment personal air samplers with PTFE-laminated membrane filters and XAD-2 resin sorbent tubes were used. Sampling flow rate was 2.0 l/min. We sampled urban air using high volume air samplers and measured the level of total PAHs in urban ambient air around the universities of the students. PAHs in filters were extracted with methylene chloride in an ultrasonic bath. Toluene was used to desorb PAHs from XAD-2 resin. After filtration with 0.45 µm filters the samples were injected into a gas chromatogram (HP-6890 Plus; Hewlett Packard, Little Falls, DE) with a flame ionization detector and a 30 mx0.32 mmx0.25 µm capillary column (HP-5 MS; Hewlett Packard). The temperatures of the injector, detector and oven were 300, 320 and 75280°C, respectively.
Analysis of urinary 1-OHP and 2-naphthol
For analysis of urinary 1-OHP and 2-naphthol concentrations we used the methods of Jongeneelen et al. (5) and Kim et al. (12), respectively. Urine samples were buffered with 0.2 M sodium acetate (pH 5.0) and hydrolyzed enzymatically using ß-glucuronidase with sulfatase activity (G-0876; Sigma, St Louis, MO) in a shaking water bath. After hydrolysis acetonitrile was added and the samples were centrifuged. A high performance liquid chromatography system was used, consisting of a pump (Waters 600E; Millipore, Milford, MA), a variable fluorescence detector (RF-10AxL; Shimadzu, Kyoto, Japan), an automatic injector (L-7200; Hitachi, Tokyo, Japan) and an integrator (Chromatopac C-R3A; Shimadzu). A 150 mm long reverse phase column (TSK gel ODS-80TM; Tosoh, Tokyo, Japan) was used for 1-OHP analysis and a 250 mm long reverse phase column (J'sphere ODS-H80; YMC, Wilmington, NC) for 2-naphthol analysis. The mobile phases were 60% acetonitrile for 1-OHP and 38% acetonitrile for 2-naphthol. The flow rate was 1 ml/min. Excitation/emission wavelengths used in the detection of 1-OHP and 2-naphthol were 242/388 nm and 277/355nm, respectively.
Determination of genotypes
Genomic DNA was isolated from venous blood using a DNA extraction kit (Promega, Madison, WI). A multiplex PCR method (20) was used to identify the genotypes for GSTM1 and GSTT1. Primers for the ß-globin gene were also included in the PCR mixture. DNA (100 ng) was amplified in a total volume of 25 µl, containing 10 pmol each primer, 2 U Taq DNA polymerase, 1.5 mM MgCl2 and PCR buffer. The amplification product was separated electrophoretically on a 2% agarose gel. GSTM1 and GSTT1 genotypes were not scored unless the PCR product amplified with the ß-globin primers was evident.
The A4889G polymorphism in exon 7 of CYP1A1 that results in an Ile
Val amino acid replacement at residue 462 was determined by the PCR restriction fragment length polymorphism method described by Oyama et al. (21). The sequences of primers were as follows: 1A1S, 5'-GAACTGCCACTTCAGCTGTCT-3'; 1A1ASHincII 5'-GAAAGACCTCCCAGCGGTCA-3'. 1A1ASHincII has a mismatch at the third residue from the 3'-end of the primer, which creates a HincII site by a PCR step when the genomic DNA is the Val/Val form of CYP1A1.
Genotyping of the RsaI polymorphism in the 5'-flanking region of CYP2E1 was carried out essentially according to methods described by Kawamoto et al. (22). The sequences of the primers were 5'-CCAGTCGAGTCTACATTTCA-3' and 5'-TTCATTCTGTCTTCTAACTGGCA-3'.
Statistical analysis
Arithmetic and geometric means and standard deviations of urinary 1-OHP and 2-naphthol concentrations were calculated. Differences in mean urinary 1-OHP and 2-naphthol levels between coke oven workers and university students were tested statistically using Student's t-test. Mean urinary 1-OHP and 2-naphthol concentrations between current smokers and non-smokers and between male and female students were also compared. Pearson correlation coefficients between level of smoking, total airborne PAH level and urinary 1-OHP and 2-naphthol concentrations and Spearman's rank correlation coefficients between dietary factors, work area and urinary 1-OHP and 2-naphthol concentrations were calculated. The statistical relationship between PAH metabolite concentrations and the polymorphisms of CYP1A1, CYP2E1, GSTM1 and GSTT1 were analyzed by Student's t-test and the Wilcoxon rank sum test. Finally, a general linear model including sex (only for university students), smoking status and the four genetic polymorphisms was analyzed, to estimate the effects of sex, smoking and the genetic polymorphisms on urinary 1-OHP and 2-naphthol concentrations.
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Results
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The distributions of age and urinary concentrations of 1-OHP and 2-naphthol are shown in Table I
. None of the female university students had a history of smoking. Both urinary 1-OHP and 2-naphthol concentrations were significantly higher in coke oven workers than in students. When comparisons were made according to smoking status, urinary 1-OHP and 2-naphthol concentrations were higher in coke oven workers who smoked habitually than in corresponding university students. We could not find any differences in urinary 1-OHP and 2-naphthol concentrations between smoking and non-smoking coke oven workers and between non-smoking male and female students. However, the geometric mean of urinary 2-naphthol was significantly higher in smoking students than in non-smoking students (Table I
).
The mean ± SD of airborne total PAH concentration was ~794-fold higher in the working environments of the coke oven workers (37.76 ± 16.19 µg/m3) than in urban air around the universities (47.54 ± 29.69 ng/m3) (Table II
).
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Table II. Distribution of total airborne PAH concentration in the working environments of coke oven workers and urban ambient air around the universities (unit: ng/m3)
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No significant correlation was found between dietary intake and concentrations of urinary PAH metabolites in coke oven workers or in students (Table III
). In smoking students, though not in smoking coke oven workers, urinary 2-naphthol concentration increased significantly with increases in the number of cigarettes smoked on the day of and on the day before sampling. Positive correlations were found between work area and urinary concentrations of 1-OHP and 2-naphthol. Urinary concentrations of 1-OHP and 2-naphthol were highest in workers working in the `top' area and lowest in `superintendent' workers. Urinary 1-OHP concentration correlated significantly with total airborne PAH level (Table III
).
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Table III. Correlation coefficients between variables and creatinine-adjusted urinary 1-OHP and 2-naphthol concentrations
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Among coke oven workers urinary 1-OHP and 2-naphthol concentrations were significantly higher in subjects with the c1/c2 or c2/c2 form of CYP2E1 than in subjects with the c1/c1 genotype. Smoking coke oven workers with a null GSTM1 genotype showed higher mean urinary 2-naphthol concentrations than those with a non-null GSTM1 genotype. No significant association was found between the CYP1A1 and GSTT1 polymorphisms and urinary PAH metabolite concentrations in coke oven workers (Tables IVVII


). In students no significant association was found using univariate analysis between PAH metabolite concentrations and the four gene polymorphisms (Tables IVVII


).
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Table IV. Geometric means and geometric standard deviations of urinary 1-OHP and 2-naphthol in coke oven workers and students with different CYP1A1 genotypes
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Table V. . Geometric means and geometric standard deviations of urinary 1-OHP and 2-naphthol in coke oven workers and students with different CYP2E1 genotypes
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Table VI. Geometric means and geometric standard deviations of urinary 1-OHP and 2-naphthol in coke oven workers and students with different GSTM1 genotypes
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Table VII. Geometric means and geometric standard deviations of urinary 1-OHP and 2-naphthol in coke oven workers and students with different GSTT1 genotypes
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In a general linear model that included sex, smoking habits and the four genetic polymorphisms as independent variables coke oven workers with the c1/c2 or c2/c2 form of CYP2E1 showed higher concentrations of urinary 1-OHP than those with the c1/c1 genotype. However, no significant factor was found in the general linear model that correlated with urinary 1-OHP concentrations among university students (Table VIII
).
Univariate analysis indicated that CYP2E1 and GSTM1 are significant independent factors influencing urinary 2-naphthol concentration among coke oven workers (Tables VVI
). In the general linear model for urinary 2-naphthol levels among university students GSTM1 and smoking were significant factors (Table IX
).
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Discussion
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Concentrations of urinary 1-OHP and 2-naphthol were significantly higher in coke oven workers than in students. The geometric means of urinary 1-OHP and 2-naphthol in this study were 85- and 3.7-fold higher, respectively, in coke oven workers than in students (Table I
). Øvrebø et al. (23) reported that the mean concentration of urinary 1-OHP was 50- and 87-fold higher in workers exposed to PAH occupationally than in two reference groups. This finding is consistent with the results of this study.
Among coke oven workers the correlation coefficient for urinary 1-OHP level and the work area was 0.720, which is greater than the corresponding value of 0.226 for 2-naphthol. The correlation coefficient for total PAH amount was larger with urinary 1-OHP concentration than with urinary 2-naphthol level (Table III
). These results indicate that 1-OHP reflects occupational PAH exposure more sensitively than does 2-naphthol. Jongeneelen et al. (24) also reported that 1-OHP formation would be a good marker for bioactivation of premutagens in coal tar and that cigarette smoking also seemed to influence urinary 1-OHP concentration, but not as a strong determinant.
We could not find any statistical difference between the urinary 1-OHP concentrations of smokers and non-smokers, either among coke oven workers or university students. However, urinary 2-naphthol levels were higher in smokers than in non-smokers among university students, but not among coke oven workers (Table I
). The differences between the geometric means of urinary 2-naphthol concentration for smokers and non-smokers were almost the same in the two groups of subjects: 2.43 and 2.39 µmol/mol creatinine for coke oven workers and university students, respectively. However, there was a large difference in the geometric means of urinary 1-OHP concentration between smokers and non-smokers. The urinary 2-naphthol concentrations among smoking students increased significantly with an increase in the number of cigarettes smoked (Table III
). Multivariate analyses that included 2-naphthol as the dependent variable indicated that smoking is not a significant independent factor among coke oven workers, but is among university students (Table IX
). These results suggest that more naphthalene than pyrene may be absorbed through smoking of tobacco and that smoking is not the major source of exposure to PAHs in coke oven workers, who are exposed to considerable levels of PAHs in their working environments.
Jansen et al. (25) and Yang et al. (15) reported that naphthalene exposure was almost exclusively due to PAH exposure via air and was therefore a good indicator of PAH exposure via air. They suggested that the concentration of naphthol, especially 2-naphthol rather than 1-naphthol, in urine would reflect the exposure to PAHs via air. Kang et al. (26) reported that the level of total suspended particulate (TSP) in urban air around Korean middle schools was significantly correlated with urinary 2-naphthol concentrations of non-smoking students in middle schools. However, no significant correlation was found between level of TSP and urinary concentration of 1-OHP glucuronide. These reports suggest that inhalation of urban air as well as cigarette smoking would increase urinary concentration of 2-naphthol.
In some previous studies with non-Asian populations the CYP1A1 polymorphism has been reported to correlate with metabolism of 1-OHP (14,27,28). However, no significant relationship between the CYP1A1 polymorphism and either urinary 1-OHP or 2-naphthol levels was found in the present study. We cannot rule out the possibility that CYP1A1 is involved in the metabolism of pyrene in the Korean population. As the mean expression level of CYP1A1 in Asian microsomes is ~35% of that in Caucasian ones (29), the mean expression level of CYP1A1 in the Korean population might not be high enough to have a significant effect on urinary 1-OHP concentrations between Koreans with the Ile/Ile form and those with the Ile/Val or Val/Val form of CYP1A1. On the other hand, CYP2E1 is expressed at higher levels in Asians than in Caucasians (29). The polymorphism of CYP2E1 was a significant factor influencing urinary levels of 1-OHP and 2-naphthol among coke oven workers in both univariate and multivariate analyses. This suggests that CYP2E1 is the major phase I enzyme metabolizing pyrene and naphthalene in Koreans. In a previous study with male Japanese workers the CYP1A1 polymorphism was not related to urinary naphthol levels and smoking subjects with c1/c2 or c2/c2 type CYP2E1 showed higher concentrations of urinary 2-naphthol than did those with the c1/c1 genotype (15). These finding agree with our present results.
GSTs have been considered important detoxicants of chemical carcinogens, including PAHs, in the diet and tobacco smoke (30). The GSTM1-null genotype increases the number of DNA adducts in coke oven workers with high PAH exposure who smoke (31). In previous studies mean levels of urinary 1-OHP (27,28,32) and naphthol (15) were higher in individuals with the GSTM1-null genotype than in those with a GSTM1-positive genotype. In the present study concentrations of urinary 2-naphthol were significantly higher in coke oven workers with the GSTM1-null genotype who smoke than in those with a GSTM1-positive genotype. This result could be explained by the fact that a deficiency in GSTM1 may stimulate the glucuronidation pathway, as a result of the accumulation of PAH derivatives that are otherwise conjugated to glutathione (33). In the present study, moreover, only ß-glucuronidase was used to hydrolyze conjugates of PAH metabolites. Therefore, glutathione-conjugated 2-naphthol could not be hydrolyzed and was not detected at the emission/excitation wavelengths used to detect unconjugated 2-naphthol. These facts suggest that GSTM1 plays an important role in the urinary excretion of low molecular weight PAHs, such as naphthalene, in occupationally exposed populations.
Higher 1-OHP glucuronide excretion has been reported in GSTT1-positive than in GSTT1-deficient Korean smokers (32). Viezzer et al. (31) reported that GSTT1-positive individuals showed elevated levels of DNA adducts compared with GSTT1-null subjects. We noted that 1-OHP levels in GSTT1-positive coke oven workers were higher than the levels in GSTT1-null coke oven workers, but the difference was not statistically significant, as in previous studies which reported that urinary 1-OHP level was not significantly influenced by polymorphic variation of GSTT1 (27,34). It is likely that the GSTT1 polymorphism does not play an important role in the metabolism of naphthalene or in the excretion of pyrene in individuals with low level exposure to PAHs.
In summary, we conclude that urinary 1-OHP is the better biomarker of human occupational exposure to PAH and that urinary 2-naphthol may be a more sensitive indicator of non-occupational inhalation exposure to PAHs, such as smoking. CYP2E1 plays an important role in the metabolism of pyrene and CYP2E1 and GSTM1 are important in the metabolism of naphthalene.
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Notes
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4 To whom correspondence should be addressed Email: kimheon{at}med.chungbuk.ac.kr 
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Acknowledgments
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This study was supported by a grant from the Korea Health 21 R&D Project, Ministry of Health and Welfare, Republic of Korea (HMP-99-M-09-0005).
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Received September 6, 2000;
revised December 19, 2000;
accepted January 24, 2001.