Early ReportAssociation between polymorphism in gene for microsomal epoxide hydrolase and susceptibility to emphysema
Introduction
The lungs are subject to oxidative stress from cigarette smoke, occupational exposure to solvents, and other chemicals and environmental pollutants. All these potential hazards contain factors (xenobiotics and oxidants) that can induce severe macromolecular, cellular, and tissue damage through direct cytotoxic effects, promotion of primary genotoxic events, or generation of reactive oxygen intermediates.
Chronic obstructive pulmonary disease (COPD) is characterised by fixed and irreversible air-flow limitation in the lungs, and emphysema is distinguished by abnormal, permanent distal air-space enlargement accompanied by destruction of lung parenchyma. Two lines of research are relevant to the study of emphysema in particular. First, some findings suggest that lung damage can be attributed to an imbalance in the endogenous protease/antiprotease equilibrium, promoting tissue hydrolysis;1–3 examples of such imbalance include the genetically determined α1-antitrypsin deficiency,3, 4 and the overexpression of elastases and collagenases that mimics the development of pulmonary emphysema.7, 8 Second, the oxidant/antioxidant theory postulates that an excess of oxidants and free radicals in the lung promotes cellular and tissue damage and is the major initiator of the disease process.9, 10 Cigarette smoke, oxidants, xenobiotics, and reactive oxygen intermediates directly inhibit antiproteases and promote cell and tissue proteolysis.1, 11, 12
Tobacco smoke is the commonest identifiable risk factor for both emphysema and COPD. Combustion products released into the respiratory tract include various highly reactive oxygen and carbon-centred species, free radicals in the vapour phase, and stable radicals in particulate matter.
Microsomal epoxide hydrolase (mEPHX) is an enzyme involved in the first-pass metabolism of highly reactive epoxide intermediates. We investigated whether genetic polymorphisms in the gene for this enzyme have any bearing on the development of oxidant-related lung disease. Epidemological studies show that mEPHX activity in the liver, lung, and peripheral blood leucocytes varies as much as 50-fold in white populations.13 Two common aberrant alleles can be detected, which confer slow and fast enzyme activity.14 We have designed PCR assays to detect these mutations and have used them to study the role of the gene in protection against oxidative damage to the lung.
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Patients and methods
203 control blood samples were obtained from the Scottish National Blood Transfusion Service. These anonymous donors were all white individuals aged between 18 and 65 years; roughly equal numbers were male and female. Because emphysema is a morphological diagnosis, we cannot be certain that some controls did not have early emphysema; however, all were clinically healthy on routine questioning and therefore met the usual criteria for blood donation.
All patients were fully investigated clinically
Results
The PCR produced amplimers of the expected size and differentiated between individual mEPHX genotypes in the study populations (figure). In the control group the slow allele was three times more common than the fast variant-13 (6%) of 203 individuals were homozygous for the exon-3 mutation (slow) and 99 (49%) were heterozygous. In comparison, the exon-4 polymorphism (fast) was detected in only 56 (28%) individuals, and only three individuals were homozygous for this variant (table 1).
The
Discussion
Our demonstration of an association between genetically defined polymorphisms in mEPHX activity and susceptibility to COPD and emphysema suggests that highly reactive epoxide intermediates may have a role in the initiation and progression of the characteristic tissue abnormalities seen in emphysema. The very slow phenotype was four to five times more common in both the COPD and emphysema groups than in controls. Also, the proportions of the emphysema group with normal and fast mEPHX phenotypes
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