Association between cytochrome P450 3A5 polymorphism and the lung function in Saskatchewan grain workers.

OBJECTIVE: The activity of the enzymes that metabolize tobacco smoke may affect the susceptibility to chronic obstructive pulmonary disease (COPD). Cytochrome P450 (CYP) 3A5 is expressed selectively over CYP3A4 in human lung, but the association between the CYP3A5 polymorphisms and the airway injury is unknown. METHODS: Two hundred and six male Saskatchewan grain workers participated in this longitudinal study, and their lung function values of forced expiratory volume in the first second (FEV1) and forced vital capacity (FVC), respiratory symptoms, smoking status, and the occupational history were analyzed. RESULTS: A significant interactive effect was observed between the CYP3A5 genotype and current smoking status on FEV1, and the annual decline rates of FEV1 and FVC in current smokers were greater among CYP3A5*1/*3 carriers than CYP3A5*3/*3 carriers (-48.7+/-16.4 vs. -31.5+/-4.7 ml/years, P=0.02; -27.4+/-18.9 vs. -5.8+/-6.5 ml/years, P=0.04). The incidences of chronic cough and COPD were also higher in current smokers with CYP3A5*1/*3 than in nonsmokers and current smokers with CYP3A5*3/*3. The adjusted odds ratios for chronic cough and COPD current smokers with CYP3A5*1/*3 versus nonsmokers with the CYP3A5*3/*3 genotype were 11.4 (P=0.009) and 4.3 (P=0.13), respectively. CONCLUSION: The results suggest that CYP3A5*1 may be a novel genetic risk factor for airway injury in smokers, and that CYP3A5 may play a role in airway injury owing to the bioactivation of chemicals in tobacco smoke.

ABCB1 polymorphisms influence the response to antiepileptic drugs in Japanese epilepsy patients.

OBJECTIVES: The efflux transporter P-glycoprotein encoded by the ATP-binding cassette (ABC)B1 gene may play a role in drug-resistant epilepsy by limiting gastrointestinal absorption and brain access of antiepileptic drugs (AEDs). Our objective was to investigate the effect of ABCB1 polymorphisms on AED responsiveness and on the pharmacokinetics of carbamazepine (CBZ) in epileptic patients with the indication for CBZ therapy. METHODS: The ABCB1 T-129C, C1236T, G2677T/A and C3435T polymorphisms were genotyped in 210 Japanese epileptics who had been prescribed AEDs, including CBZ, for longer than 2 years. Haplotype and diplotype frequencies were estimated by expectation-maximization algorithm. Drug resistance was determined by the presence of seizures. Association of the polymorphisms with the risk of drug resistance was estimated by logistic regression analysis and the odds ratios (ORs) were adjusted for the clinical factors affecting the outcome of AED therapy. CBZ concentrations to the dose (C/D) ratios were compared among the ABCB1 polymorphisms. RESULTS: Drug-resistant patients were more likely to have the T allele (OR [95% confidence interval (CI)], 2.02 [1.14-3.58]) and the TT genotype at C3435T (OR [95% CI], 3.64 [1.16-11.39]), and the TT genotype at G2677T/A (OR vs the GG genotype [95% CI], 3.43 [1.01-11.72]). The frequency of the T-T-T haplotype at C1236T, G2677T/A and C3435T was significantly higher (OR [95% CI], 1.84 [1.03-3.30]), and the CC-GG-CC diplotype was lower (OR [95% CI], 0.09 [0.01-0.85]) in the drug-resistant patients than in the drug-responsive patients. None of the ABCB1 polymorphisms were observed to influence the C/D ratios of CBZ. CONCLUSION: We demonstrated that ABCB1 polymorphisms may influence the AED responsiveness without significant changes in the plasma concentrations of CBZ. Our findings were the inverse of previous results in European epileptics, thus the influence of ABCB1 polymorphisms on the AED responsiveness and/or the P-glycoprotein activity may vary among races.