Myeloperoxidase (MPO) −463G→A Reduces MPO Activity and DNA Adduct Levels in Bronchoalveolar Lavages of Smokers
- Frederik J. Van Schooten1,
- Agnes W. Boots1,
- Ad M. Knaapen1,
- Roger W. L. Godschalk1,
- Lou M. Maas1,
- Paul J. A. Borm2,
- Marjolein Drent3 and
- Jan A. Jacobs4
- 1Department of Health Risk Analysis and Toxicology, Maastricht University, Maastricht, The Netherlands; 2Particle Research Core, Research Institute for Environmental Health, Düsseldorf, Germany; and Departments of 3Respiratory Medicine and 4Medical Microbiology, University Hospital Maastricht, Maastricht, The Netherlands
- Request for reprints:
Frederik J. Van Schooten, Department of Health Risk Analysis and Toxicology, Maastricht University, P. O. Box 616, 6200 MD, Maastricht, The Netherlands. Phone: 31-43-3881100; Fax: 31-43-3884641. E-mail: F.vanschooten{at}grat.unimaas.nl
Abstract
The myeloperoxidase (MPO) −463G→A genetic polymorphism is associated with a reduced risk for lung cancer, but the underlying mechanism is not yet elucidated. Therefore, the impact of this polymorphism on MPO activity and lipophilic DNA adducts was studied in respectively bronchoalveolar lavage (BAL) fluid and cells, from 106 smoking Caucasian lung patients. MPO activity was determined spectrophotometrically, aromatic DNA adducts by 32P-postlabeling and MPO genotypes by RFLP analysis. Frequencies of MPO −463AA (13%), MPO −463AG (36%), and MPO −463GG (51%) were in line with earlier observations. MPO activity/neutrophil was lower in MPO −463AA (median 0.04 pU/cell) than in MPO −463AG (median 0.07 pU/cell) and MPO −463GG (median 0.14 pU/cell; P = 0.059) individuals. DNA adducts in BAL cells were measured in 11 MPO −463AA subjects and equal numbers of MPO −463AG and MPO −463GG subjects matched for smoking, age, gender, and clinical diagnosis. DNA adduct levels in MPO −463AA individuals (median 0.62 adducts/108 nucleotides) were lower than in MPO −463AG (median 1.51 adducts/108 nucleotides) and MPO −463GG (median 3.26 adducts/108 nucleotides; P = 0.003) subjects. Overall, no significant correlation was observed between amount of inhaled tar/day and DNA adduct levels. However, correlations improved considerably on grouping according to the MPO genotype; MPO −463AA subjects were the least responsive (R2 = 0.73, slope = 0.4, P = 0.01) followed by MPO −463AG subjects (R2 = 0.70, slope = 1.3, P = 0.01) and MPO −463GG patients (R2 = 0.67, slope = 2.8, P = 0.02). These data demonstrate that MPO −463AA/AG genotypes are associated with (a) reduced MPO activity in BAL fluid and (b) reduced smoking-related DNA adduct levels in BAL cells in a gene-dose manner. These data provide a plausible biological explanation for the reduced risk for lung cancer as observed in MPO −463AA/AG compared with MPO −463GG subjects.
Footnotes
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The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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Note: Present address of A.W. Boots: Department of Pharmacology and Toxicology, Maastricht University, P. O. Box 616, 6200 MD, Maastricht, The Netherlands.
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- Accepted January 23, 2004.
- Received November 4, 2003.
- Revision received January 19, 2004.
