Alkylating and oxidative stresses in smoking and non-smoking patients with COPD: Implications for lung carcinogenesis

Abstract

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.

Keywords: COPD; Inflammation; Methylated DNA damage; NNAL; NNK; Oxidative DNA/RNA damage.

Figure 1.

Distributions of cotinine, free NNAL, total NNAL and ratio of free NNAL/total NNAL in COPD smokers and control smokers. Each point represents an individual subject and the horizontal lines represent geometric mean values. The comparison was performed by Mann-Whitney U test.

Figure 2.

Distributions of alkylating stress biomarkers (N7-MeGua and N3-MeAde) in (A) smokers and (B) non-smokers. Each point represents an individual subject and the horizontal lines represent geometric mean values. The comparison was performed by Mann-Whitney U test.

Figure 3.

Distributions of oxidative stress biomarkers (8-oxoGua, 8-oxodGuo and 8-oxoGuo) in (A) smokers and (B) non-smokers. Each point represents an individual subject and the horizontal lines represent geometric mean values. The comparison was performed by Mann-Whitney U test.

Figure 4.

Distributions of cotinine, free NNAL, total NNAL and ratio of free NNAL/total NNAL in COPD smokers with stages 1-2 and stages 3-4 disease. Each point represents an individual subject and the horizontal lines represent geometric mean values. The comparison was performed by Mann-Whitney U test.