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Communications to the Editor |

Xenobiotic Enzymes and Genetics of COPD FREE TO VIEW

Shinji Teramoto, MD; Takeo Ishii, MD; Hiroshi Yamamoto, MD; Yasuhiro Yamaguchi, MD; Takeshi Matsuse, MD
Author and Funding Information

Affiliations: The University of Tokyo Hospital, Tokyo, Japan,  Otsuka Maryland Research Institute, Rockville, MD

Correspondence to: Shinji Teramoto, MD, Department of Geriatric Medicine, The University of Tokyo Hospital, 7–3-1 Hongo Bunkyo-ku, Tokyo, 113-8655 Japan; e-mail: shinjit-tky@umin.ac.jp, fax 03–5800-6530



Chest. 2005;127(1):408-409. doi:10.1378/chest.127.1.408
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To the Editor:

In a recent issue of CHEST (May 2004), Molfino1 reported that current knowledge of the genetics of COPD is limited. He clearly indicated that the inconsistent results from association studies of candidate genes and COPD may be due to the phenotype definitions used or to ethnic differences among the patients in the studies. That is why some preliminary conclusions can be drawn.

Although he cited many articles on candidate gene-association studies and linkage analyses, which have been reported for COPD patients, the pathogenesis of COPD associated with the xenobiotic enzyme has been totally neglected. It has been suggested that genetic polymorphisms in xenobiotic enzymes may have a role in individual susceptibility to oxidant-related lung disease.24 The first-pass metabolism of foreign compounds in the lung is an important protective mechanism against oxidative stress. The polymorphisms in the genes for cytochrome P450, microsomal epoxide hydrolase (mEPHX) and glutathione S-transferase (GST) P1, which are the enzymes involved in this protective process, had some bearing on individual susceptibility to the development of COPD.24 As shown in Figure 1 , xenobiotics are closely associated with the oxidant-antioxidant imbalance, which is one of the two major hypotheses in the pathogenesis of smoke-related COPD. Further, oxidant-antioxidant imbalance causes the oxidative inactivation of antiproteinases, alveolar epithelial injury, increased sequestration of neutrophils in the pulmonary microvasculature, and gene expression of proinflammatory mediators.

Each puff of a cigarette contains 1017 free radicals and about 4,000 substrates, including carcinogenic agents and other possible causative agents of COPD such as volatile aldehydes and hydrogen cyanide.5Thus, defects in the detoxification of these reactive species may predispose smokers to airflow obstruction and emphysema. Indeed, mEPHX activity was significantly higher in patients with COPD, when compared to healthy control subjects.6These findings have been supported by the study of Sandford and colleagues,7 who assessed a well-characterized cohort of patients from the Lung Health Study.

We have reported that the genetic polymorphism of exon 5 of smokers with GSTP1 is associated with the development of COPD in smokers.3 Because the GSTP1/Ile105 genotype is predominantly found in smokers with COPD (72%), but not in smokers without airflow limitation (52%), the GSTP1/Ile105 genotype may be less protective against the xenobiotics in tobacco smoke. Recent data8further support the idea that the GSTP1/Ile105 homozygote is associated with an increase in IgE and histamine after challenge with diesel exhaust particles and allergens. Although cigarette smoking is the most important risk factor for the development of COPD, allergic airway inflammation, long-standing asthma, air pollutants, diesel exhaust particles, and xenobiotics also may cause irreversible airflow limitation such as COPD. It has been reported9 that tunnel workers being exposed to gases and particles from blasting and diesel exhausts are likely to develop COPD. Therefore, subjects exposed to diesel exhaust particles are susceptible to the accelerated decline of lung function, resulting in COPD.

There is growing evidence for the role of xenobiotics and antioxidant imbalance in the pathogenesis of airflow obstruction, which is supported by the results of association studies between COPD and variants in epoxide hydrolase and GSTs that detoxify free radicals and other tobacco products.1014 Before these associations are generally accepted, they must be subjected to scrutiny with further association studies in terms of ethnicity and COPD phenotypes.

Figure Jump LinkFigure 1. Hypothesis of genetic susceptibility to COPD.Grahic Jump Location

References

Molfino, NA (2004) Gentics of COPD.Chest125,1929-1940. [CrossRef] [PubMed]
 
Koyama, H, Geddes, DM Genes, oxidative stress, and the risk of chronic obstructive pulmonary disease.Thorax1998;53(suppl),S10-S14
 
Ishii, T, Matsuse, T, Teramoto, S, et al Glutathione S-transferase P1 (GSTP1) polymorphism in patients with chronic obstructive pulmonary disease.Thorax1999;54,693-696. [CrossRef] [PubMed]
 
Minematsu, N, Nakamura, H, Iwata, M, et al Association of CYP2A6 deletion polymorphism with smoking habit and development of pulmonary emphysema.Thorax2003;58,623-628. [CrossRef] [PubMed]
 
Hoffmann, D, Hoffmann, I The changing cigarette, 1950–1995.J Toxicol Environ Health1997;50,307-364. [CrossRef] [PubMed]
 
Smith, CA, Harrison, DJ Association between polymorphism in gene for microsomal epoxide hydrolase and susceptibility to emphysema.Lancet1997;350,630-633. [CrossRef] [PubMed]
 
Sandford, AJ, Chagani, T, Weir, TD, et al Susceptibility genes for rapid decline of lung function in the lung health study.Am J Respir Crit Care Med2001;163,469-473. [PubMed]
 
Gilliland, FD, Li, YF, Saxon, A, et al Effect of glutathione-S-transferase M1 and P1 genotypes on xenobiotic enhancement of allergic responses: randomized, placebo-controlled crossover study.Lancet2004;363,119-125. [CrossRef] [PubMed]
 
Trupin, L, Earnest, G, San Pedro, M, et al The occupational burden of chronic obstructive pulmonary disease.Eur Respir J2003;22,462-469. [CrossRef] [PubMed]
 
Cheng, SL, Yu, CJ, Chen, CJ, et al Genetic polymorphism of epoxide hydrolase and glutathione S-transferase in COPD.Eur Respir J2004;23,818-824. [CrossRef] [PubMed]
 
Ishii, T, Matsuse, T, Igarashi, H, et al Tobacco smoke reduces viability in human lung fibroblasts: protective effect of glutathione S-transferase P1.Am J Physiol2001;280,L1189-L1195
 
Teramoto, S, Kume, H The role of nuclear factor-κ B activation in airway inflammation following adenovirus infection and COPD.Chest2001;119,1294-1295. [CrossRef] [PubMed]
 
Teramoto, S, Ishii, T No association of tumor necrosis factor-α gene polymorphism and COPD in Caucasian smokers and Japanese smokers.Chest2001;119,315-316. [CrossRef] [PubMed]
 
Teramoto, S, Yamamoto, H, Yamaguchi, Y, et al Global burden of COPD in Japan and Asia,Lancet2003;362,1764-1765
 
To the Editor:

I fully agree with Dr. Teramoto’s comments that xenobiotic enzymes seem to play a role in protecting the lung compartment but that their exact role in the pathogenesis of COPD is not clear. This is mentioned in my review1 (pages 1932 to 1933). Most of the findings described by Dr. Teramoto were also mentioned and referenced in my review.1

Nevertheless, I would like to propose to Dr. Teramoto that, despite these findings, genetics may only take us this far. A more complete interpretation of how genes play a role in human lung disease requires a higher level of integration with computational genomics, proteomics, and lung physiology. Thus, isolated findings in one gene or gene family, while helpful in moving the field forward, may not provide a comprehensive answer.2

References
Molfino, NA Genetics of COPD.Chest2004;125,1929-1940. [CrossRef] [PubMed]
 
Molfino, NA Lung function evolution and respiratory symptoms [editorial].Arch Bronconeumol2004;40,429-430. [PubMed]
 

Figures

Figure Jump LinkFigure 1. Hypothesis of genetic susceptibility to COPD.Grahic Jump Location

Tables

References

Molfino, NA (2004) Gentics of COPD.Chest125,1929-1940. [CrossRef] [PubMed]
 
Koyama, H, Geddes, DM Genes, oxidative stress, and the risk of chronic obstructive pulmonary disease.Thorax1998;53(suppl),S10-S14
 
Ishii, T, Matsuse, T, Teramoto, S, et al Glutathione S-transferase P1 (GSTP1) polymorphism in patients with chronic obstructive pulmonary disease.Thorax1999;54,693-696. [CrossRef] [PubMed]
 
Minematsu, N, Nakamura, H, Iwata, M, et al Association of CYP2A6 deletion polymorphism with smoking habit and development of pulmonary emphysema.Thorax2003;58,623-628. [CrossRef] [PubMed]
 
Hoffmann, D, Hoffmann, I The changing cigarette, 1950–1995.J Toxicol Environ Health1997;50,307-364. [CrossRef] [PubMed]
 
Smith, CA, Harrison, DJ Association between polymorphism in gene for microsomal epoxide hydrolase and susceptibility to emphysema.Lancet1997;350,630-633. [CrossRef] [PubMed]
 
Sandford, AJ, Chagani, T, Weir, TD, et al Susceptibility genes for rapid decline of lung function in the lung health study.Am J Respir Crit Care Med2001;163,469-473. [PubMed]
 
Gilliland, FD, Li, YF, Saxon, A, et al Effect of glutathione-S-transferase M1 and P1 genotypes on xenobiotic enhancement of allergic responses: randomized, placebo-controlled crossover study.Lancet2004;363,119-125. [CrossRef] [PubMed]
 
Trupin, L, Earnest, G, San Pedro, M, et al The occupational burden of chronic obstructive pulmonary disease.Eur Respir J2003;22,462-469. [CrossRef] [PubMed]
 
Cheng, SL, Yu, CJ, Chen, CJ, et al Genetic polymorphism of epoxide hydrolase and glutathione S-transferase in COPD.Eur Respir J2004;23,818-824. [CrossRef] [PubMed]
 
Ishii, T, Matsuse, T, Igarashi, H, et al Tobacco smoke reduces viability in human lung fibroblasts: protective effect of glutathione S-transferase P1.Am J Physiol2001;280,L1189-L1195
 
Teramoto, S, Kume, H The role of nuclear factor-κ B activation in airway inflammation following adenovirus infection and COPD.Chest2001;119,1294-1295. [CrossRef] [PubMed]
 
Teramoto, S, Ishii, T No association of tumor necrosis factor-α gene polymorphism and COPD in Caucasian smokers and Japanese smokers.Chest2001;119,315-316. [CrossRef] [PubMed]
 
Teramoto, S, Yamamoto, H, Yamaguchi, Y, et al Global burden of COPD in Japan and Asia,Lancet2003;362,1764-1765
 
Molfino, NA Genetics of COPD.Chest2004;125,1929-1940. [CrossRef] [PubMed]
 
Molfino, NA Lung function evolution and respiratory symptoms [editorial].Arch Bronconeumol2004;40,429-430. [PubMed]
 
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