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Shin SS, Yang EH, Lee HC, Moon SH, Ryoo JH. Association of metabolites of benzene and toluene with lipid profiles in Korean adults: Korean National Environmental Health Survey (2015-2017). BMC Public Health 2022; 22:1917. [PMID: 36242012 PMCID: PMC9569087 DOI: 10.1186/s12889-022-14319-x] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2022] [Accepted: 10/07/2022] [Indexed: 11/23/2022] Open
Abstract
Background Environmental exposure to benzene and toluene is a suspected risk factor for metabolic disorders among the general adult population. However, the effects of benzene and toluene on blood lipid profiles remain unclear. In this study, we investigated the association between urinary blood lipid profiles and metabolites of benzene and toluene in Korean adults. Methods We analyzed the data of 3,423 adults from the Korean National Environmental Health Survey Cycle 3 (2015–2017). We used urinary trans,trans-muconic acid (ttMA) as a biomarker of benzene exposure, and urinary benzylmercapturic acid (BMA) as an indicator of toluene exposure. Multivariate logistic regression analyses were performed to explore the association between blood lipid profiles and urinary metabolites of benzene and toluene. Additionally, we examined the linear relationship and urinary metabolites of benzene and toluene between lipoprotein ratios using multivariate regression analyses. Results After adjusting for covariates, the fourth quartile (Q4) of ttMA [odds ratio (OR) (95% confidence interval, CI = 1.599 (1.231, 2.077)] and Q3 of BMA [OR (95% CI) = 1.579 (1.129, 2.208)] were associated with an increased risk of hypertriglyceridemia. However, the Q4 of urinary ttMA [OR (95% CI) = 0.654 (0.446, 0.961)] and Q3 of urinary BMA [OR (95% CI) = 0.619 (0.430, 0.889)] decreased the risk of a high level of low-density lipoprotein cholesterol (LDL-C). Higher urinary ttMA levels were positively associated with the ratio of triglycerides to high-density lipoproteins [Q4 compared to Q1: β = 0.11, 95% CI: (0.02, 0.20)]. Higher urinary metabolite levels were negatively associated with the ratio of low-density lipoprotein to high-density lipoprotein [Q4 of ttMA compared to reference: β = -0.06, 95% CI: (-0.11, -0.01); Q4 of BMA compared to reference: β = -0.13, 95% CI: (-0.19, -0.08)]. Conclusion Benzene and toluene metabolites were significantly and positively associated with hypertriglyceridemia. However, urinary ttMA and BMA levels were negatively associated with high LDL-C levels. These findings suggest that environmental exposure to benzene and toluene disrupts lipid metabolism in humans. Supplementary Information The online version contains supplementary material available at 10.1186/s12889-022-14319-x.
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Affiliation(s)
- Soon Su Shin
- Department of Preventive Medicine, Graduate School, Kyung Hee University, Seoul, Republic of Korea
| | - Eun Hye Yang
- Department of Occupational and Environmental Medicine, Kyung Hee University Hospital, Seoul, Republic of Korea
| | - Hyo Choon Lee
- Department of Occupational and Environmental Medicine, Kyung Hee University Hospital, Seoul, Republic of Korea
| | - Seong Ho Moon
- Department of Occupational and Environmental Medicine, Kyung Hee University Hospital, Seoul, Republic of Korea
| | - Jae-Hong Ryoo
- Department of Occupational and Environmental Medicine, School of Medicine, Kyung Hee University, Seoul, Republic of Korea.
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Weng Z, Shi Y, Suda M, Yanagiba Y, Kawamoto T, Nakajima T, Wang RS. Inhalation exposure to low levels of ethyl tertiary butyl ether: Its genetic effects were significantly modified by ALDH2 activity. ENVIRONMENTAL AND MOLECULAR MUTAGENESIS 2019; 60:145-153. [PMID: 30474146 DOI: 10.1002/em.22256] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/24/2018] [Revised: 09/26/2018] [Accepted: 09/30/2018] [Indexed: 06/09/2023]
Abstract
Previous experiments showed that high concentrations of ethyl tertiary butyl ether (ETBE) exposure (500-5,000 ppm) significantly resulted in DNA damages in aldehyde dehydrogenase 2 (Aldh2) knockout (KO) mice. This study was aimed to verify the genotoxic effects in three genetic types, Aldh2 KO, heterogeneous (HT), and wild type (WT), of mice exposed to lower concentrations of ETBE (50-500 ppm) by inhalation. Histopathology assessments in the livers, measurements of genotoxic biomarkers in blood and livers, and urinary 8-hydroxydeoxyguanosion (8-OH-dG) for the oxidative DNA damage of whole body were performed. Significant histopathological changes and DNA strand breaks both in hepatocytes and leukocytes were found in HT and KO male mice exposed to ≥200 ppm ETBE, but not in 50 ppm ETBE. 8-OH-dG levels either in liver or urine were higher in the HT and KO male mice exposed to ≥200 ppm ETBE. The pathological and genetic effects of ETBE were almost at the same extents for HT and KO mice. Thus, 50 ppm could be the no observed adverse effect level for ETBE in HT and KO male mice, which was far lower than the 500 ppm in WT mice. These results suggested that decrease and deficiency of ALDH2 activity would significantly increase the sensitivity to ETBE-induced genotoxicity as well as hepatotoxic effects after exposure even to low concentrations of ETBE. Environ. Mol. Mutagen. 60: 145-153, 2019. © 2018 Wiley Periodicals, Inc.
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Affiliation(s)
- Zuquan Weng
- College of Biological Science and Engineering, Fuzhou University, Fuzhou, China
- National Institute of Occupational Safety and Health, Kawasaki, Japan
| | - Yuhong Shi
- College of Biological Science and Engineering, Fuzhou University, Fuzhou, China
| | - Megumi Suda
- National Institute of Occupational Safety and Health, Kawasaki, Japan
| | - Yukie Yanagiba
- National Institute of Occupational Safety and Health, Kawasaki, Japan
| | - Toshihiro Kawamoto
- Department of Environmental Health, University of Occupational and Environmental Health, Kitakyushu, Japan
| | - Tamie Nakajima
- College of Life and Health Sciences, Chubu University, Nagoya, Japan
| | - Rui-Sheng Wang
- National Institute of Occupational Safety and Health, Kawasaki, Japan
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3
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Matsumoto A. [Importance of an Aldehyde Dehydrogenase 2 Polymorphism in Preventive Medicine]. Nihon Eiseigaku Zasshi 2018; 73:9-20. [PMID: 29386454 DOI: 10.1265/jjh.73.9] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Unlike genetic alterations in other aldehyde dehydrogenase (ALDH) isozymes, a defective ALDH2 polymorphism (rs671), which is carried by almost half of East Asians, does not show a clear phenotype such as a shortened life span. However, impacts of a defective ALDH2 allele, ALDH2*2, on various disease risks have been reported. As ALDH2 is responsible for the detoxification of endogenous aldehydes, a negative effect of this polymorphism is predicted, but bidirectional effects have been actually observed and the mechanisms underlying such influences are often complex. One reason for this complexity may be the existence of compensatory aldehyde detoxification systems and the secondary effects of these systems. There are many issues to be addressed with regard to the ALDH2 polymorphism in the field of preventive medicine, including the following concerns. First, ALDH2 in the fetal stage plays a role in aldehyde detoxification; therefore, prenatal health effects of environmental aldehyde exposure are of concern for ALDH2*2-carrying fetuses. Second, ALDH2*2 carriers are at high risk of drinking-related cancers. However, their drinking habits result in less worsening of physiological findings, such as energy metabolism index and liver functions, compared with non-ALDH2*2 carriers, and therefore opportunities to detect excessive drinking can be lost. Third, personalized medicine such as personalized prescriptions for ALDH2*2 carriers will be required in the clinical setting, and accumulation of evidence is awaited. Lastly, since the ALDH2 polymorphism is not considered in workers' limits of exposure to aldehydes and their precursors, efforts to lower exposure levels beyond legal standards are required.
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Affiliation(s)
- Akiko Matsumoto
- Department of Social Medicine, Saga University School of Medicine
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4
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Significant association between decreased ALDH2 activity and increased sensitivity to genotoxic effects in workers occupationally exposed to styrene. Oncotarget 2016; 7:38224-38234. [PMID: 27224914 PMCID: PMC5122384 DOI: 10.18632/oncotarget.9502] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2015] [Accepted: 05/01/2016] [Indexed: 12/15/2022] Open
Abstract
ALDH2 is involved in the metabolism of styrene, a widely used industrial material, but no data are available regarding the influence of this enzyme on the metabolic fate as well as toxic effects of this chemical. In this study, we recruited 329 workers occupationally exposed to styrene and 152 unexposed controls. DNA strand breaks, DNA-base oxidation in leukocytes and urinary 8-hydroxydeoxyguanosine (8-OH-dG) were assayed as biomarkers to measure genotoxic effects. Meanwhile, we examined the genetic polymorphisms, including ALDH2, EXPH1, GSTM1, GSTT1 and CYP2E1, and also analyzed the levels of styrene exposure through detecting urinary styrene metabolites and styrene concentration in air. In terms of DNA damage, the three genotoxic biomarkers were significantly increased in exposed workers as compared with controls. And the styrene-exposed workers with inactive ALDH2 *2 allele were subjected to genotoxicity in a higher degree than those with ALDH2 *1/*1 genotype. Also, lower levels of urinary styrene metabolites (MA + PGA) were observed in styrene-exposed workers carrying ALDH2 *2 allele, suggesting slower metabolism of styrene. The polymorphisms of other enzymes showed less effect. These results suggested that styrene metabolism and styrene-induced genotoxicity could be particularly modified by ALDH2 polymorphisms. The important role of ALDH2 indicated that the accumulation of styrene glycoaldehyde, a possible genotoxic intermediate of styrene, could account for the genotoxicity observed, and should be taken as an increased risk of cancer.
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Kim KW, Won YL, Ko KS. Ethnic Differences in the Metabolism of Toluene: Comparisons between Korean and Foreign Workers Exposed to Toluene. Toxicol Res 2015; 31:25-32. [PMID: 25874030 PMCID: PMC4395652 DOI: 10.5487/tr.2015.31.1.025] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2015] [Revised: 03/19/2015] [Accepted: 03/23/2015] [Indexed: 12/12/2022] Open
Abstract
The objectives of this study were to investigate the individual characteristics, lifestyle habits, exposure levels, and genetic diversity of xenobiotic-metabolizing enzymes involved in toluene metabolism in Korean and foreign workers exposed to toluene at a manufacturing plant. This study was conducted to determine the effects of culture or ethnicity on toluene metabolism. The results showed that blood and urinary toluene concentrations were dependent on the level of exposure to toluene. We analyzed the correlation between toluene metabolism and genetic diversity in glutathione S-transferase (GST) (M1), GSTT1, and cytochrome p-450 (CYP) 2E1*5 as well as lifestyle habits (smoking, drinking, and exercise habits). The results revealed significant correlations between toluene metabolism and GSTM1 and GSTT1 genetic diversity, as well as smoking and exercise.
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Affiliation(s)
- Ki-Woong Kim
- Occupational Safety and Health Research Institute, KOSHA, Ulsan, Korea
| | - Young Lim Won
- Occupational Safety and Health Research Institute, KOSHA, Ulsan, Korea
| | - Kyung Sun Ko
- Occupational Safety and Health Research Institute, KOSHA, Ulsan, Korea
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6
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Kim YD, Eom SY, Zhang YW, Kim H, Park JD, Yu SD, Lee CH, Arashidani K, Kawamoto T, Kim H. Modification of the relationship between urinary 8-OHdG and hippuric acid concentration by GSTM1, GSTT1, and ALDH2 genotypes. Hum Exp Toxicol 2010; 30:338-42. [PMID: 20488846 DOI: 10.1177/0960327110371813] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Urinary hippuric acid (HA) has been widely used as a biological marker of occupational exposure to toluene, although it is no longer valid for low levels of toluene exposure. Toluene exposure is known to induce oxidative DNA damage and the metabolism is affected by genetic polymorphisms of some metabolizing enzymes. Therefore, genetic polymorphisms of these metabolizing enzymes must be considered in the evaluation of oxidative stress caused by toluene exposure. We evaluated the relationship between urinary 8-hydroxydeoxyguanosine (8-OHdG), a marker of oxidative DNA damage, and urinary HA in individuals without occupational exposure to toluene and characterized the possible roles of GSTM1, GSTT1, and aldehyde dehydrogenase 2 (ALDH2) genotypes in the relationships between these markers. In this study, we enrolled 92 healthy Koreans. Urinary HA and 8-OHdG levels were measured and the correlations between them were statistically tested according to the GSTM1, GSTT1, and ALDH2 genotypes. HA did not significantly correlate with urinary 8-OHdG in overall subjects. However, the correlation between them showed a statistical significance in individuals with GSTM1-null, GSTT1-null, and ALDH2 *2/*2 genotypes (r = 0.766, p < 0.01). This study shows that the relationship between urinary HA and 8-OHdG concentration is modified by genetic polymorphisms of some metabolizing enzymes such as GSTM1, GSTT1, and ALDH2.
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Affiliation(s)
- Yong-Dae Kim
- Department of Preventive Medicine and Medical Research Institute, College of Medicine, Chungbuk National University, Cheongju, Chungbuk, South Korea
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7
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Affiliation(s)
- Heon Kim
- Department of Preventive Medicine, College of Medicine, Chungbuk National University, Cheongju, Korea
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8
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Ginsberg G, Smolenski S, Neafsey P, Hattis D, Walker K, Guyton KZ, Johns DO, Sonawane B. The influence of genetic polymorphisms on population variability in six xenobiotic-metabolizing enzymes. JOURNAL OF TOXICOLOGY AND ENVIRONMENTAL HEALTH. PART B, CRITICAL REVIEWS 2009; 12:307-333. [PMID: 20183525 DOI: 10.1080/10937400903158318] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/28/2023]
Abstract
This review provides variability statistics for polymorphic enzymes that are involved in the metabolism of xenobiotics. Six enzymes were evaluated: cytochrome P-450 (CYP) 2D6, CYP2E1, aldehyde dehydrogenase-2 (ALDH2), paraoxonase (PON1), glutathione transferases (GSTM1, GSTT1, and GSTP1), and N-acetyltransferases (NAT1 and NAT2). The polymorphisms were characterized with respect to (1) number and type of variants, (2) effects of polymorphisms on enzyme function, and (3) frequency of genotypes within specified human populations. This information was incorporated into Monte Carlo simulations to predict the population distribution and describe interindividual variability in enzyme activity. The results were assessed in terms of (1) role of these enzymes in toxicant activation and clearance, (2) molecular epidemiology evidence of health risk, and (3) comparing enzyme variability to that commonly assumed for pharmacokinetics. Overall, the Monte Carlo simulations indicated a large degree of interindividual variability in enzyme function, in some cases characterized by multimodal distributions. This study illustrates that polymorphic metabolizing systems are potentially important sources of pharmacokinetic variability, but there are a number of other factors including blood flow to liver and compensating pathways for clearance that affect how a specific polymorphism will alter internal dose and toxicity. This is best evaluated with the aid of physiologically based pharmacokinetic (PBPK) modeling. The population distribution of enzyme activity presented in this series of articles serves as inputs to such PBPK modeling analyses.
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Affiliation(s)
- Gary Ginsberg
- Connecticut Department of Public Health, Hartford, 06134, USA.
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9
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Kunugita N, Isse T, Oyama T, Kitagawa K, Ogawa M, Yamaguchi T, Kinaga T, Kawamoto T. Increased frequencies of micronucleated reticulocytes and T-cell receptor mutation in Aldh2 knockout mice exposed to acetaldehyde. J Toxicol Sci 2008; 33:31-6. [PMID: 18303182 DOI: 10.2131/jts.33.31] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/02/2022]
Abstract
Aldehyde dehydrogenase-2 (ALDH2) metabolizes acetaldehyde produced from ethanol into acetate and plays a major role in the oxidation of acetaldehyde in vivo. About half of all Japanese people have inactive ALDH2. We generated homozygous Aldh2 null (Aldh2-/-) mice by gene targeting knockout as a model of ALDH2-deficient humans. To investigate the mutagenicity of acetaldehyde, a micronucleus assay and a T-cell receptor (TCR) gene mutation assay were performed in Aldh2-/- mice and wild-type (Aldh2 +/+) mice exposed to acetaldehyde. The mice were continuously exposed to 125 and 500 ppm of acetaldehyde vapor for 2 weeks. Another group was orally administered 100 mg/kg once a day for 2 weeks continuously. The mice were killed after 2 weeks of exposure to acetaldehyde, and the frequency of micronucleated reticulocytes was measured by flow cytometry. We also observed the incidence of TCR gene mutations in T-lymphocytes by measuring the variant CD3(-CD4+) expression by flow cytometry. The frequency of micronucleated reticulocytes induced by acetaldehyde was significantly increased in Aldh2 -/- mice, but not in Aldh2 +/+ mice. TCR mutant frequency was also associated with acetaldehyde exposure in Aldh2-/ - mice, especially after oral administration; however, it was not associated with acetaldehyde exposure in Aldh2 +/+ mice. In conclusion, Aldh2 -/- mice showed high sensitivity in the micronuclei and TCR mutation assays compared with Aldh2 +/+ mice after exposure to acetaldehyde.
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Affiliation(s)
- Naoki Kunugita
- Department of Health Information Science, School of Health Sciences, University of Occupational and Environmental Health, Iseigaoka, Kitakyushu, Japan.
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10
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Lee HS, Yang M. Applications of CYP-450 expression for biomonitoring in environmental health. Environ Health Prev Med 2008; 13:84-93. [PMID: 19568886 DOI: 10.1007/s12199-007-0009-6] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2007] [Accepted: 09/15/2007] [Indexed: 11/25/2022] Open
Abstract
Cytochrome P450s (CYPs) are one of the first steps in the metabolism of xenobiotics, such as polycyclic aromatic hydrocarbons (PAHs), which are bioactivated into carcinogens. As such, changes in CYP expression are potential biomarkers in human biomonitoring applications. For the proper biomonitoring of environmental toxicants, it is important to understand the biological relevance of each biomarker and the associations among the biomarkers for uses as exposure, effects, and susceptibility biomarkers. Here, we have reviewed various aspects of CYPs for biomonitoring environmental health in terms of the CYP substrates, such as PAHs, aromatic amines, benzene/toluene, and tobacco smoking-related nitrosamines. This review also includes association studies between CYP phenotypical alterations and other exposure, susceptibility, and effect biomarkers. The association studies were mainly performed in CYP gene-transfected cells and noninvasive human biospecies, such as urine and peripheral blood. In conclusion, we suggest that phenotypical alterations in CYPs with exposure to environmental toxicants are useful as susceptibility or effect biomarkers, particularly when the phenotype-related genotypes are unknown.
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Affiliation(s)
- Ho-Sun Lee
- Department of Toxicology, College of Pharmacy, Sookmyung Women's University, 53-12 Chungpa-dong 2 Ka, Yongsan-Ku, Seoul, Republic of Korea
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11
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Yi B, Yang JY, Yang M. Past and future applications of CYP450-genetic polymorphisms for biomonitoring of environmental toxicants. JOURNAL OF ENVIRONMENTAL SCIENCE AND HEALTH. PART C, ENVIRONMENTAL CARCINOGENESIS & ECOTOXICOLOGY REVIEWS 2007; 25:353-377. [PMID: 18000786 DOI: 10.1080/10590500701704037] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/25/2023]
Abstract
Cytochrome P450s (CYPs) are a huge gene superfamily of heme enzymes involved in xenobioitc as well as endobiotic metabolism. They play a critical role in adaptation to environmental changes for survival of living organisms. In addition, the huge environmental loads of human-made chemicals are biotransformed into bioactive or detoxified forms by CYPs. Thus, CYPs have been used for biomonitoring of environmental pollutants, screening of their metabolisms and exploring remedy. In particular, the induction or inhibition of CYPs has been applied to exposure monitoring of environmental toxicants, which are biotransformed by CYPs. This review considers past and future applications of CYP-genetic polymorphisms as susceptibility biomarkers for biomonitoring. Furthermore, we suggest the needs for further understanding of the characteristics of each CYP isozyme, consideration of real-life exposures such as mixed contamination with various chemicals, and incorporation of the presence of other phase I and phase II enzymes, for proper applications of CYP polymorphisms on biomonitoring.
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Affiliation(s)
- Bitna Yi
- Sookmyung Women's University, College of Pharmacy, Seoul, Korea
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12
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Alvarez‐Leite EM, Duarte A, Barroca MM, Silveira JN. Possible Effects of Drinking and Smoking Habits on Hippuric Acid Levels in Urine of Adults with No Occupational Toluene Exposure. J Occup Health 2006. [DOI: 10.1539/joh.41.112] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Affiliation(s)
- Edna Maria Alvarez‐Leite
- Department of Clinical Chemistry and ToxicologyCollege of Pharmacy, Federal University of Minas Gerais‐UFMGBrazil
| | - Alessandra Duarte
- Department of Clinical Chemistry and ToxicologyCollege of Pharmacy, Federal University of Minas Gerais‐UFMGBrazil
| | - Marcia Martins Barroca
- Department of Clinical Chemistry and ToxicologyCollege of Pharmacy, Federal University of Minas Gerais‐UFMGBrazil
| | - Josianne Nicacio Silveira
- Department of Clinical Chemistry and ToxicologyCollege of Pharmacy, Federal University of Minas Gerais‐UFMGBrazil
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Ishikawa H, Miyatsu Y, Kurihara K, Yokoyama K. Gene-environmental interactions between alcohol-drinking behavior and ALDH2 and CYP2E1 polymorphisms and their impact on micronuclei frequency in human lymphocytes. Mutat Res 2006; 594:1-9. [PMID: 16126235 DOI: 10.1016/j.mrfmmm.2005.07.005] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2005] [Revised: 06/29/2005] [Accepted: 07/13/2005] [Indexed: 05/04/2023]
Abstract
Ethanol is converted to acetaldehyde by alcohol dehydrogenase (ADH), cytochrome p4502E1 (CYP2E1) and catalase. This metabolite is then detoxified by aldehyde dehydrogenase 2 (ALDH2), a key enzyme in the elimination of acetaldehyde, via further oxidation to acetic acid. The toxic effects of acetaldehyde are well documented and may be partially mediated by genotoxic damage. In the present study, we investigated the effects of alcohol-drinking behavior and genetic polymorphisms in two different genes (ALDH2 and CYP2E1) on the micronuclei (MN) frequency in 248 healthy Japanese men. Genotyping was performed by PCR-RFLP analysis. The ALDH2 variant (deficient type) was significantly associated with an increased MN frequency in subjects drinking more than three times/wk, while habitual drinkers with wild-type CYP2E1 also had a significantly increased MN frequency. Furthermore, when the subjects were divided into eight groups according to their drinking frequency and genotypes of ALDH2 and CYP2E1, we found that habitual drinkers with homozygous CYP2E1*1/*1 and heterozygous ALDH2*1/*2 or homozygous ALDH2*2/*2 showed the highest mean MN frequency. In the present study, we found clear associations among ALDH2 and CYP2E1 gene polymorphisms, alcohol-drinking behavior and genotoxic effects in a healthy Japanese population. Therefore, analysis of the polymorphisms of alcohol-metabolizing enzymes may lead to elucidation of the mechanism(s) for individual susceptibilities to the toxicity of ethanol metabolites.
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Affiliation(s)
- Hitoshi Ishikawa
- Department of Public Health and Occupational Medicine, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie 514-8507, Japan.
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Ogawa M, Isse T, Oyama T, Kunugita N, Yamaguchi T, Kinaga T, Narai R, Matsumoto A, Kim YD, Kim H, Uchiyama I, Kawamoto T. Urinary 8-hydoxydeoxyguanosine (8-OHdG) and plasma malondialdehyde (MDA) levels in Aldh2 knock-out mice under acetaldehyde exposure. INDUSTRIAL HEALTH 2006; 44:179-83. [PMID: 16610557 DOI: 10.2486/indhealth.44.179] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/08/2023]
Abstract
To clarify the carcinogenicity of acetaldehyde when associated with ALDH (aldehyde dehydrogenase) 2 polymorphism, Aldh2 knock-out (Aldh2-/-) mice and their wild type (Aldh2+/+) mice were exposed to two different concentrations of acetaldehyde (125 ppm and 500 ppm) for two weeks. Aldh2-/- mice, which have the same genetic background as C57BL/6J (wild mice) except for the Aldh2 gene, were used as models of humans who lack ALDH2 activity. Urinary 8-hydroxydeoxyguanosine (8-OHdG) and plasma malondialdehyde (MDA) levels were measured as indicators of oxidative DNA damage and lipid peroxidation, respectively. At 125 ppm acetaldehyde exposure for 12 d, urinary 8-OHdG levels in Aldh2+/+ mice did not increase. However, urinary 8-OHdG levels in Aldh2-/- mice were slightly increased by the end of the exposure. On the other hand, plasma MDA levels did not increase in either Aldh2-/- orAldh2+/+ mice. At 500 ppm, urinary 8-OHdG levels in both Aldh2-/- and Aldh2+/+ mice significantly increased after 6 and 12 d, but there was no genetic difference. On the other hand, plasma MDA levels in Aldh2+/+ and Aldh2-/- mice did not increase at either 125 ppm or 500 ppm after two weeks of exposure. In conclusion, it is suspected that DNA was damaged by acetaldehyde inhalation, and that susceptibility to acetaldehyde varies according to Aldh2 genotype.
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Affiliation(s)
- Masanori Ogawa
- Department of Environmental Health, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu, Fukuoka 807-8555, Japan
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Nan HM, Song YJ, Yun HY, Park JS, Kim H. Effects of dietary intake and genetic factors on hypermethylation of the hMLH1 gene promoter in gastric cancer. World J Gastroenterol 2005; 11:3834-41. [PMID: 15991278 PMCID: PMC4504881 DOI: 10.3748/wjg.v11.i25.3834] [Citation(s) in RCA: 51] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: Hypermethylation of the promoter of the hMLH1 gene, which plays an important role in mismatch repair during DNA replication, occurs in more than 30% of human gastric cancer tissues. The purpose of this study was to investigate the effects of environmental factors, genetic polymorphisms of major metabolic enzymes, and microsatellite instability on hypermethylation of the promoter of the hMLH1 gene in gastric cancer.
METHODS: Data were obtained from a hospital-based, case-control study of gastric cancer. One hundred and ten gastric cancer patients and 220 age- and sex-matched control patients completed a structured questionnaire regarding their exposure to environmental risk factors. Hypermethylation of the hMLH1 gene promoter, polymorphisms of the GSTM1, GSTT1, CYP1A1, CYP2E1, ALDH2 and L-myc genes, microsatellite instability and mutations of p53 and Ki-ras genes were investigated.
RESULTS: Both smoking and alcohol consumption were associated with a higher risk of gastric cancer with hypermethylation of the hMLH1 gene promoter. High intake of vegetables and low intake of potato were associated with increased likelihood of gastric cancer with hypermethylation of the hMLH1 gene promoter. Genetic polymorphisms of the GSTM1, GSTT1, CYP1A1, CYP2E1, ALDH2, and L-myc genes were not significantly associated with the risk of gastric cancer either with or without hypermethylation in the promoter of the hMLH1 gene. Hypermethylation of the hMLH1 promoter was significantly associated with microsatellite instability (MSI): 10 of the 14 (71.4%) MSI-positive tumors showed hypermethylation, whereas 28 of 94 (29.8%) the MSI-negative tumors were hypermethylated at the hMLH1 promoter region. Hypermethylation of the hMLH1 gene promoter was significantly inversely correlated with mutation of the p53 gene.
CONCLUSION: These results suggest that cigarette smoking and alcohol consumption may influence the development of hMLH1-positive gastric cancer. Most dietary factors and polymorphisms of GSTM1, GSTT1, CYP1A1, CYP2E1, ALDH2, and L-myc genes are not independent risk factors for gastric cancer with hyperme-thylation of the hMLH1 promoter. These data also suggest that there could be two or more different molecular pathways in the development of gastric cancer, perhaps involving tumor suppression mechanisms or DNA mismatch repair.
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Affiliation(s)
- Hong-Mei Nan
- Department of Preventive Medicine, College of Medicine, Chungbuk National University, 12 Kaeshin-dong, Hungdok-gu, Cheongju-si, Chungbuk 361-763, Republic of Korea
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Nan HM, Park JW, Song YJ, Yun HY, Park JS, Hyun T, Youn SJ, Kim YD, Kang JW, Kim H. Kimchi and soybean pastes are risk factors of gastric cancer. World J Gastroenterol 2005; 11:3175-81. [PMID: 15929164 PMCID: PMC4316045 DOI: 10.3748/wjg.v11.i21.3175] [Citation(s) in RCA: 73] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/03/2004] [Revised: 11/04/2004] [Accepted: 01/13/2005] [Indexed: 02/07/2023] Open
Abstract
AIM This case-control study investigated the effects of kimchi, soybean paste, fresh vegetables, nonfermented alliums, nonfermented seafood, nonfermented soybean foods, and the genetic polymorphisms of some metabolic enzymes on the risk of gastric cancer in Koreans. METHODS We studied 421 gastric cancer patients and 632 age- and sex-matched controls. Subjects completed a structured questionnaire regarding their food intake pattern. Polymorphisms of cytochrome P450 1A1 (CYP1A1), cytochrome P450 2E1 (CYP2E1), glutathione S-transferase mu 1 (GSTM1), glutathione S-transferase theta 1 (GSTT1) and aldehyde dehydrogenase 2 (ALDH2) were investigated. RESULTS A decreased risk of gastric cancer was noted among people with high consumption of nonfermented alliums and nonfermented seafood. On the other hand, consumption of kimchi, and soybean pastes was associated with increased risk of gastric cancer. Individuals with the CYP1A1 Ile/Val or Val/Val genotype showed a significantly increased risk for gastric cancer. Increased intake of kimchi or soybean pastes was a significant risk factor for the CYP1A1 Ile/Ile, the CYP2E1 c1/c1, the GSTM1 non-null, the GSTT1 non-null, or the ALDH2 *1/*1 genotype. In addition, eating soybean pastes was associated with the increased risk of gastric cancer in individuals with the GSTM1 null type. Nonfermented alliums were significant in individuals with the CYP1A1 Ile/Ile, the CYP2E1 c1/c2 or c2/c2, the GSTT1 null, the GSTT1 non-null, or the ALDH2 *1/*2 or *2/*2 genotype, nonfermented seafood was those with the CYP1A1 Ile/Ile, the CYP2E1 c1/c1, the ALDH2 *1/*1 genotype or any type of GSTM1 or GSTT1. In homogeneity tests, the odds ratios of eating kimchi for gastric cancer according to the GSTM1 or GSTT1 genotype were not homogeneous. CONCLUSION Kimchi, soybean pastes, and the CYP1A1 Ile/Val or Val/Val are risk factors, and nonfermented seafood and alliums are protective factors against gastric cancer in Koreans. Salt or some chemicals contained in kimchi and soybean pastes, which are increased by fermentation, would play important roles in the carcinogenesis of stomach cancer. Polymorphisms of the CYP1A1, CYP2E1, GSTM1, GSTT1, and ALDH2 genes could modify the effects of some environmental factors on the risk of gastric cancer.
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Affiliation(s)
- Hong-Mei Nan
- Department of Preventive Medicine, College of Medicine, Chungbuk National University, 12 Kaeshin-dong, Hungdok-gu, Cheongju-si, Chungbuk 361-763, Korea
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17
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Kim YD, Lee CH, Nan HM, Kang JW, Kim H. Effects of genetic polymorphisms in metabolic enzymes on the relationships between 8-hydroxydeoxyguanosine levels in human leukocytes and urinary 1-hydroxypyrene and 2-naphthol concentrations. J Occup Health 2004; 45:160-7. [PMID: 14646291 DOI: 10.1539/joh.45.160] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
This study was designed to investigate the relationship between environmental exposure to polycyclic aromatic hydrocarbons (PAHs) and oxidative stress, and to evaluate the effects of cigarette smoking and the genetic polymorphisms of CYP1A1, CYP2E1, GSTM1, NAT2 and UGT1A6 on the relationship. The subjects of this study were 105 healthy Korean males without occupational exposure to PAHs. The 8-hydroxydeoxyguanosine (8-OHdG) level in leukocytes, and urinary 1-hydroxypyrene (1-OHP) and 2-naphthol concentrations, were measured by high-performance liquid chromatography. Genetic polymorphisms of CYP1A1, CYP2E1, GSTM1, NAT2 and UGT1A6 were identified by PCR and PCR-RFLP methods. The 8-OHdG level showed a significant correlation with the 1-OHP concentration in all subjects (p<.001) and in smokers (p<.01), and with the 2-naphthol level in non-smokers (p<.01). The 8-OHdG level was significantly higher in smoking rapid acetylators than in smoking slow or intermediate acetylators, and in individuals with the UGT1A6 wild-type than in those with the UGT1A6 mutant genotype. Significant positive correlations between 8-OHdG and 1-OHP concentrations were found in subjects with every genotype of the CYP1A1 and CYP2E1 genes, with the GSTM1 null-type, with the NAT2 genotype of a rapid acetylator, and with the UGT1A6 wild-type, respectively. The urinary 2-naphthol level significantly correlated with the 8-OHdG level only in subjects with the GSTM1 null-type. In conclusion, there is a significant correlation between the 8-OHdG level in leukocytes and the urinary 1-OHP concentration in the population not occupationally exposed to PAHs. This relationship is affected by genetic polymorphisms in PAH metabolic enzymes.
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Affiliation(s)
- Yong-Dae Kim
- Department of Preventive Medicine, College of Medicine, Chungbuk National University, South Korea
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18
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Ernstgård L, Sjögren B, Warholm M, Johanson G. Sex differences in the toxicokinetics of inhaled solvent vaporsin humans 1. m-Xylene. Toxicol Appl Pharmacol 2003; 193:147-57. [PMID: 14644617 DOI: 10.1016/j.taap.2003.08.004] [Citation(s) in RCA: 19] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
The aim of this study was to evaluate possible sex differences in the inhalation toxicokinetics of m-xylene vapor. Seventeen healthy volunteers (nine women and eight men) were exposed to m-xylene (200 mg/m3) and to clean air (control exposure) on different occasions during 2 h of light physical exercise (50 W). The chosen level corresponds to the occupational exposure limit (8-h time weighted average) in Sweden. m-Xylene was monitored up to 24 h after exposure in exhaled air, blood, saliva, and urine by headspace gas chromatography. m-Methylhippuric acid (a metabolite of m-xylene) was analyzed in urine by high-performance liquid chromatography. Body fat and lean body mass (LBM) were estimated from sex-specific equations using bioelectrical impedance, body weight, height, and age. Genotypes and/or phenotypes of cytochromes P450 2E1 and 1A1, glutathione transferases M1 and P1, and epoxide hydrolase were determined. The toxicokinetic profile in blood was analyzed using a two-compartment population model. The area under the concentration-time curve (AUC) of m-xylene in exhaled air postexposure was larger in women than in men. In addition, the excretion via exhaled air was significantly higher in women when correcting for body weight or LBM. In contrast, the men had a significantly higher volume of distribution, excretion of m-methylhippuric acid in urine, and AUC of m-xylene in urine. The toxicokinetic analyses revealed no differences between subjects of different metabolic genotypes or phenotypes. In conclusion, the study indicates small sex differences in the inhalation toxicokinetics of m-xylene, which can be explained by body build.
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Affiliation(s)
- Lena Ernstgård
- Work Environment Toxicology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
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19
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Ginsberg G, Smolenski S, Hattis D, Sonawane B. Population distribution of aldehyde dehydrogenase-2 genetic polymorphism: implications for risk assessment. Regul Toxicol Pharmacol 2002; 36:297-309. [PMID: 12473414 DOI: 10.1006/rtph.2002.1591] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
The role of genetic polymorphisms in modulating xenobiotic metabolism and susceptibility to cancer and other health effects has been suggested in numerous studies. However, risk assessments have generally not used this information to characterize population variability or adjust risks for susceptible subgroups. This paper focuses upon the aldehyde dehydrogenase-2 (ALDH2) system because it exemplifies the pivotal role genetic polymorphisms can play in determining enzyme function and susceptibility. Allelic variants in ALDH2 cause decreased ability to clear acetaldehyde and other aldehyde substrates, with homozygous variants (ALDH2*2/2) having no activity and heterozygotes (ALDH2*1/2) having intermediate activity relative to the predominant wild type (ALDH2*1/1). These polymorphisms are associated with increased buildup of acetaldehyde following ethanol ingestion and increased immediate symptoms (flushing syndrome) and long-term cancer risks. We have used Monte Carlo simulation to characterize the population distribution of ALDH2 allelic variants and inter-individual variability in aldehyde internal dose. The nonfunctional allele is rare in most populations, but is common in Asians such that 40% are heterozygotes and 5% are homozygote variants. The ratio of the 95th or 99th percentiles of the Asian population compared to the median of the U.S. population is 14- to 26-fold, a variability factor that is larger than the default pharmacokinetic uncertainty factor (3.2-fold) commonly used in risk assessment. Approaches are described for using ALDH2 population distributions in physiologically based pharmacokinetic-Monte Carlo refinements of risk assessments for xenobiotics which are metabolized to aldehyde intermediates (e.g., ethanol, toluene, ethylene glycol monomethyl ether).
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Affiliation(s)
- Gary Ginsberg
- Connecticut Department of Public Health, Hartford, 06134, USA.
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20
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Yang M, Coles BF, Delongchamp R, Lang NP, Kadlubar FF. Effects of the ADH3, CYP2E1, and GSTP1 genetic polymorphisms on their expressions in Caucasian lung tissue. Lung Cancer 2002; 38:15-21. [PMID: 12367788 DOI: 10.1016/s0169-5002(02)00150-2] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
Abstract
Individual differences in lung cancer susceptibility should be considered for effective lung cancer prevention. We investigated the CYP2E1, ADH3, and GSTP1 genetic polymorphisms that biotransform xenobiotic carcinogens, and variations of their enzyme activity in Caucasian lung tissues (N=28), and found a variant distribution in pulmonary ADH and CYP2E1 activity. The ADH3*1/*1 subjects (N=8) showed significantly higher ADH activity than ADH3*2/*2 (N=3) subjects (P<0.01). On the other hand, we found a 5-fold variation in the pulmonary CYP2E1 activity using a sensitive HLPC/EC based technique. A subject with the CYP2E1-c/t allele showed 2-fold higher CYP2E1 activity than subjects with the c/c allele (N=14). GSTP1 expression comprised 83% of the total pulmonary GSTs. However, neither the GSTP1 polymorphism, nor other lifestyle factors, such as age, gender, smoking status, were found to be associated with pulmonary GST expression. In conclusion, subjects with the ADH3*1 allele showed higher ADH activity and acetaldehyde-DNA adducts in lung than other subjects; thus, the ADH3*1 allele could be considered a risk factor for lung cancer.
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Affiliation(s)
- Mihi Yang
- Department of Preventive Medicine, Cancer Research Institute, College of Medicine, Seoul National University, 28 Yongon-Dong, Chongno-Gu, 110-799, Seoul, Republic of Korea.
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21
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Saito T, Takeichi S. Simultaneous detection of hippuric acid and methylhippuric acid in urine by Empore disk and gas chromatography-mass spectrometry. J Pharm Biomed Anal 2002; 30:365-70. [PMID: 12191723 DOI: 10.1016/s0731-7085(02)00268-6] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
A method is described for the determination of hippuric acid (HA) and o-, m-, and p-methylhippuric acids (o-, m-, p-MHAs) in urine using solid-phase extraction and gas chromatography-mass spectrometry (GC-MS). The extraction procedure uses an Empore disk, derivatized into the respective trimethyl silyl derivatives. All metabolites including the internal standard (I.S.) were clearly able to be analyzed by the DB-17 column. The calibration curves for the four acids show linearity in the range of 5-70 microg/ml. The detection limit of each acid was 1.0-2.5 microg/ml.
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Affiliation(s)
- Takeshi Saito
- Department of Forensic Medicine, Tokai University School of Medicine, Bohseidai, Isehara, Kanagawa 259-1193, Japan.
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22
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Lee CY, Lee JY, Kang JW, Kim H. Effects of genetic polymorphisms of CYP1A1, CYP2E1, GSTM1, and GSTT1 on the urinary levels of 1-hydroxypyrene and 2-naphthol in aircraft maintenance workers. Toxicol Lett 2001; 123:115-24. [PMID: 11641039 DOI: 10.1016/s0378-4274(01)00374-5] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
This study was undertaken to investigate the effects of genetic polymorphisms of the cytochrome P450 1A1 (CYP1A1) and 2E1 (CYP2E1), and glutathione S-transferases mu (GSTM1) and theta (GSTT1) on urinary 1-hydroxypyrene and 2-naphthol levels, and to estimate the level of exposure to polycyclic aromatic hydrocarbons (PAHs) in aircraft maintenance workers. In 218 Korean aircraft maintenance workers, the geometric means of urinary 1-hydroxypyrene and 2-naphthol were 0.32 and 3.25 micromol/mol creatinine, respectively. These urinary concentrations were approximately at the upper limit of the general population. Mean urinary 2-naphthol concentrations were significantly different between smokers and non-smokers. CYP1A1 and GSTM1 were statistically significant in analyses on both 1-hydroxypyrene and 2-naphthol levels among smokers. The results suggest that smoking has more profound effects on urinary PAH metabolites than does genetic polymorphisms in this population, and that CYP1A1 and GSTM1 activity might be related to the metabolism of 1-hydroxypyrene and 2-naphthol.
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Affiliation(s)
- C Y Lee
- Department of Preventive Medicine, School of Medicine, Kyungbuk National University, 101 Dongin-dong 2 Ga, Jung-gu, 700-422, Taegu, South Korea
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23
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Raikhlin-Eisenkraft B, Hoffer E, Baum Y, Bentur Y. Determination of urinary hippuric acid in toluene abuse. JOURNAL OF TOXICOLOGY. CLINICAL TOXICOLOGY 2001; 39:73-6. [PMID: 11327230 DOI: 10.1081/clt-100102883] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Abstract
BACKGROUND Volatile substance abuse is practiced mainly by adolescents and young adults. Its effects are central nervous system excitation followed by central nervous system depression, at times accompanied by seizures. It may cause sudden death as a result of ventricular arrhythmias, reflex vagal inhibition, respiratory depression, and anoxia. Chronic toxicity may involve the nervous system, heart, kidney, and liver. Toluene-based adhesives are among the most commonly inhaled substances. CASE REPORT A 14-year-old female presented with confusion, hallucinations, and intermittent laughing and crying after having inhaled contact glue several times daily in the course of 5 days. Her condition improved within 3 h. Urinary hippuric acid was 93.9 g/g creatinine indicating heavy toluene exposure (biological exposure index, BEI, is 1.6 g/g creatinine). CONCLUSION In this patient, urinary hippuric acid was a biomarker for her toluene abuse.
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Affiliation(s)
- B Raikhlin-Eisenkraft
- Israel Poison Information Center, Rambam Medical Center, The Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa
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24
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Haeseler G, Mamarvar M, Bufler J, Dengler R, Hecker H, Aronson JK, Piepenbrock S, Leuwer M. Voltage-dependent blockade of normal and mutant muscle sodium channels by benzylalcohol. Br J Pharmacol 2000; 130:1321-30. [PMID: 10903972 PMCID: PMC1572205 DOI: 10.1038/sj.bjp.0703447] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022] Open
Abstract
1. We studied the effects of benzylalcohol on heterologously expressed wild type (WT), paramyotonia congenita (R1448H) and hyperkalaemic periodic paralysis (M1360V) mutant alpha-subunits of human skeletal muscle sodium channels. 2. Benzylalcohol blocked rested channels at -150 mV membrane potential, with an ECR(50) of 5.3 mM in wild type, 5.1 mM in R1448H, and 6.2 mM in M1360V. When blockade was assessed at -100 mV, the ECR(50) was reduced in R1448H (2 mM) compared with both wild type (4.3 mM; P<0.01) and M1360V (4.3 mM). 3. Membrane depolarization before the test depolarization significantly promoted benzylalcohol-induced sodium channel blockade. The values of K(D) for the fast-inactivated state derived from benzylalcohol-induced shifts in steady-state availability curves were 0.66 mM in wild type and 0.58 mM in R1448H. In the presence of slow inactivation induced by 2.5 s depolarizing prepulses, the ECI(50) for benzylalcohol-induced current inhibition was 0.59 mM in wild type and 0.53 mM in R1448H. 4. Recovery from fast inactivation was prolonged in the presence of drug in all clones. 5. Benzylalcohol induced significant frequency-dependent block at stimulating frequencies of 10, 50, and 100 Hz in all clones. 6. Our results clearly show that benzylalcohol is an effective blocker of muscle sodium channels in conditions that are associated with membrane depolarization. Mutants that enter voltage-dependent inactivation at more hyperpolarized membrane potentials compared with wild type are more sensitive to inhibitory effects at the normal resting potential.
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Affiliation(s)
- G Haeseler
- Department of Anaesthesiology, Hannover Medical School, Hannover, Germany
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25
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Kitagawa K, Kunugita N, Katoh T, Yang M, Kawamoto T. The significance of the homozygous CYP2A6 deletion on nicotine metabolism: a new genotyping method of CYP2A6 using a single PCR-RFLP. Biochem Biophys Res Commun 1999; 262:146-51. [PMID: 10448083 DOI: 10.1006/bbrc.1999.1182] [Citation(s) in RCA: 57] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
A convenient and specific CYP2A6 genotyping method was developed in this study. This method consisting of a single PCR-RFLP is capable of resolving the genotype into either CYP2A6*1 (wild type), CYP2A6*2, or CYP2A6*3. Among 252 Japanese persons genotyped, 241 were genotyped as the wild type, 1 as an unknown variant, and none as either CYP2A6*2 or CYP2A6*3. A homozygous deletion was found in the 10 remaining subjects. To clarify the metabolic significance of this deletion in the whole human body, urinary cotinine, the principal metabolite of nicotine, was analyzed subsequent to smoking. Cumulated urinary cotinine excretion in the homozygously CYP2A6-deleted individuals was about one-seventh compared to the control group (wild type). This study provides a firm experimental basis for correlating genotypic characterization of CYP2A6 with phenotypic expression of nicotine metabolism.
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Affiliation(s)
- K Kitagawa
- Department of Environmental Health, School of Health Science, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu, 807-8555, Japan
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26
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Pierce CH, Lewandowski TA, Dills RL, Morgan MS, Wessels MA, Shen DD, Kalman DA. A comparison of 1H8- and 2H8-toluene toxicokinetics in men. Xenobiotica 1999; 29:93-108. [PMID: 10078842 DOI: 10.1080/004982599238830] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/16/2022]
Abstract
1. To examine the bioequivalence of an isotope-labelled tracer to study toxicant disposition, we conducted 33 controlled human exposures to a mixture of 50 ppm 1H8-toluene and 50 ppm 2H8-toluene for 2 h, and measured concentrations in blood and breath, and metabolite levels in urine for 100 h post-exposure. 2. A physiologically based kinetic (PBK) model found that compared with 1H8-toluene, 2H8-toluene had a 6.4+/-13% (mean+/-SD) lower AUC, a 6.5+/-13% higher systemic clearance (1.46+/-0.27 versus 1.38+/-0.25 l/h-kg), a 17+/-22% larger terminal volume of distribution (66.4+/-14 versus 57.2+/-10 l/kg) and a 9.7+/-26% longer terminal half-life (38+/-12 versus 34+/-10 h) (p < 0.05 for all comparisons). 3. The higher 2H8-toluene clearance may have been due to an increased rate of ring oxidation, consistent with the 17% higher observed fraction of 2H5- versus 1H5-cresol metabolites in urine. 4. The larger terminal volume and half-lives for 2H8-toluene suggested a higher adipose tissue/blood partition coefficient. 5. Observed isotope differences were small compared with interindividual differences in 1H8-toluene kinetics from previous studies. 6. The PBK model allowed us to ascribe observed isotope differences in solvent toxicokinetics to underlying physiologic mechanisms.
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Affiliation(s)
- C H Pierce
- Department of Environmental Health, University of Washington, Seattle 98195, USA
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Abstract
This article reviews, with an emphasis on human experimental data, factors known or suspected to cause changes in the toxicokinetics of organic solvents. Such changes in the toxicokinetic pattern alters the relation between external exposure and target dose and thus may explain some of the observed individual variability in susceptibility to toxic effects. Factors shown to modify the uptake, distribution, biotransformation, or excretion of solvent include physical activity (work load), body composition, age, sex, genetic polymorphism of the biotransformation, ethnicity, diet, smoking, drug treatment, and coexposure to ethanol and other solvents. A better understanding of modifying factors is needed for several reasons. First, it may help in identifying important potential confounders and eliminating negligible ones. Second, the risk assessment process may be improved if different sources of variability between external exposures and target doses can be quantitatively assessed. Third, biological exposure monitoring may be also improved for the same reason.
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Affiliation(s)
- A Löf
- Department of Occupational Medicine, National Institute for Working Life, Solna, Sweden
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Abstract
One in ten tobacco smokers develops bronchogenic carcinoma over a lifetime. The study of susceptibility of an individual and a population to lung cancer traditionally has been limited to the study of tobacco smoke dose and family history of cancer. New insights into lung carcinogenesis have made the study of molecular markers of risk possible in human populations in the emerging field of molecular epidemiology. This review summarizes data addressing the relationships of human lung cancer to polymorphisms of phase I procarcinogen-activating and phase II-deactivating enzymes and intermediate biomarkers of DNA mutation, such as DNA adducts, oncogene and tumor suppressor gene mutation, and polymorphisms. These parameters are reviewed as they relate to tobacco smoke exposure, procarcinogen metabolizing polymorphisms, and the presence of lung cancer. Problem areas in biomarker validation, such as cross-sectional data interpretation; tissue source, race, statistical power, and ethical implications are addressed.
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Affiliation(s)
- S D Spivack
- Laboratory of Human Toxicology and Molecular Epidemiology, New York State Department of Health, Albany, NY 12201-0509, USA
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29
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Affiliation(s)
- M Harper
- SKC, Inc., Eighty Four, Pennsylvania 15390, USA
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