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Myeloperoxidase (MPO) –463GA Reduces MPO Activity and DNA Adduct Levels in Bronchoalveolar Lavages of Smokers

¹ Department of Health Risk Analysis and Toxicology, Maastricht University, Maastricht, The Netherlands; ² Particle Research Core, Research Institute for Environmental Health, Düsseldorf, Germany; and Departments of ³ Respiratory Medicine and ⁴ Medical 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

The myeloperoxidase (MPO) –463GA 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.

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