Chronic obstructive pulmonary disease (
COPD) is a disease characterized by chronic
inflammation and irreversible
airway obstruction. Cigarette smoking is the predominant risk factor for developing
COPD. It is well-known that the
COPD is also strongly associated with an increased risk of developing
lung cancer. Cigarette
smoke contains elevated concentrations of
oxidants and various
carcinogens (e.g., tobacco-derived
nitrosamines) that can cause oxidative and alkylating stresses, which can also arise from
inflammation. However, it is surprising that, except for oxidative stress, little information is available on the burden of alkylating stress and the detoxification efficiency of tobacco-derived
carcinogens in
COPD patients. In this study, we used LC-MS/MS to measure the archetypical tobacco-specific carcinogenic
4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), its major metabolite,
4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), three
biomarkers of oxidative stress (8-oxo-7,8-dihydroguanine, 8-oxoGua;
8-oxo-7,8-dihydro-2'-deoxyguanosine, 8-oxodGuo; 8-oxo-7,8-dihydroguanosine, 8-oxoGuo) and two
biomarkers of alkylating stress (N7-methylguanine, N7-MeGua and N3-methyladenine, N3-MeAde), in the urine of smoking and non-smoking
COPD patients and healthy controls. Our results showed that not only was oxidative stress significantly elevated in the
COPD patients compared to the controls, but also alkylating stress. Significantly, levels of alkylating stress (i.e., N7-MeGua) were highly correlated with the
COPD severity and not affected by age and smoking status. Furthermore,
COPD smokers had significantly higher ratios of free NNAL to the total NNAL than control smokers, implying a lower detoxification efficiency of NNK in
COPD smokers. This ratio was even higher in
COPD smokers with stages 3-4 than in
COPD smokers with stages 1-2. Taken together, our results demonstrated that the detoxification efficiency of tobacco-derived
carcinogens (e.g., NNK) was associated with the pathogenesis and possibly the progression of
COPD. In addition to oxidative stress, alkylating stress derived from chronic
inflammation appears to be also dominant in
COPD patients.