Pathway Analysis of Global Metabolomic Profiles Identified Enrichmentof Caffeine Energy and Arginine Metabolism in Smokers but Not Moist SnuffConsumers

摘要

Existing US epidemiological data demonstrate that consumption of smokeless tobacco, particularly moist snuff, is less harmful than cigarette smoking. However, the molecular and biochemical changes due to moist snuff consumption relative to smoking remain incompletely understood. We previously reported that smokers (SMK) exhibit elevated oxidative stress and inflammation relative to moist snuff consumers (MSC) and non-tobacco consumers (NTC), based on metabolomic profiling data of saliva, plasma, and urine from MSC, SMK, and NTC. In this study, we investigated the effects of tobacco consumption on additional metabolic pathways using pathway-based analysis tools. To this end, metabolic pathway enrichment analysis and topology analysis were performed through pair-wise comparisons of global metabolomic profiles of SMK, MSC, and NTC. The analyses identified >8 significantly perturbed metabolic pathways in SMK compared with NTC and MSC in all 3 matrices. Among these differentially enriched pathways, perturbations of caffeine metabolism, energy metabolism, and arginine metabolism were mostly observed. In comparison, fewer enriched metabolic pathways were identified in MSC compared with NTC (5 in plasma, none in urine and saliva). This is consistent with our transcriptomics profiling results thatshow no significant differences in peripheral blood mononuclear cell geneexpression between MSC and NTC. These findings, taken together with our previousbiochemical, metabolomic, and transcriptomic analysis results, provide a betterunderstanding of the relative changes in healthy tobacco consumers, anddemonstrate that chronic cigarette smoking, relative to the use of smokelesstobacco, results in more pronounced biological changes, which could culminate insmoking-related diseases.