Global metabolomic profiles reveal differences in oxidative stress and inflammation pathways in smokers and moist snuff consumers

Background: The existing US epidemiological data show that long-term cigarette smokers are at higher risk of developing serious diseases relative to moist snuff consumers. To understand the effects of tobacco consumption, global metabolomic profiles were generated. Here, we describe metabolomic changes in oxidative stress and inflammation pathways. Methods: Matching plasma, urine, and saliva samples from chronic/long-term smokers (SMK), moist snuff consumers (MSC), and non-tobacco consumers (NTC), 40 subjects in each cohort, were collected in a crosssectional biomarker discovery study. Untargeted metabolomics and data analyses were performed using Metabolon’s proprietary technology. Results: Several biochemicals that significantly differed between study cohorts were identified in all three matrices, with most metabolites found in urine. Random forest analyses of the metabolomes grouped study subjects with a high accuracy and indicated that nicotine and its metabolites primarily drive separation between the NTC and MSC; otherwise, metabolomic profiles of NTC and MSC are more similar to each other, and SMK appear to manifest a distinct metabolomic profile. SMK exhibit lower levels of antioxidants, changes in glutathione metabolism and purine degradation pathways, docosahexaenoate, arachidonate, and 12-hydroxyeicosatetraenoic acid, suggesting increased oxidative stress and inflammation relative to MSC and NTC. Conclusions: Metabolomic profiles show that while SMK and MSC cohorts exhibit higher levels of nicotine and its metabolites, SMK manifest evidence of increased oxidative stress and inflammation relative to MSC and NTC. These observed biochemical changes in the SMK could be likely due to the combustion-related toxicants present in cigarette smoke. Impact: Several differentiating metabolites identified herein could be utilized as potential biomarkers of effect. Further, the metabolomic profiles improve our understanding of biological changes in tobacco consumers.