Multiplatform serum metabolic phenotyping combined with pathway mapping to identify biochemical differences in smokers.

AIM: Determining perturbed biochemical functions associated with tobacco smoking should be helpful for establishing causal relationships between exposure and adverse events. RESULTS: A multiplatform comparison of serum of smokers (n = 55) and never-smokers (n = 57) using nuclear magnetic resonance spectroscopy, UPLC-MS and statistical modeling revealed clustering of the classes, distinguished by metabolic biomarkers. The identified metabolites were subjected to metabolic pathway enrichment, modeling adverse biological events using available databases. Perturbation of metabolites involved in chronic obstructive pulmonary disease, cardiovascular diseases and cancer were identified and discussed. CONCLUSION: Combining multiplatform metabolic phenotyping with knowledge-based mapping gives mechanistic insights into disease development, which can be applied to next-generation tobacco and nicotine products for comparative risk assessment.

A comparative in vitro kinetic study of [14C]-eugenol and [14C]-methyleugenol activation and detoxification in human, mouse, and rat liver and lung fractions.

Eugenol is a natural alkenylbenzene compound used in a variety of consumer products. There is limited evidence for the carcinogenicity of eugenol to experimental animals. However, in vitro tests for the genotoxic potential of eugenol have on occasion reported a positive result. In contrast, the structurally related alkenylbenzene methyleugenol is consistently reported as genotoxic and carcinogenic in vitro and in vivo. Metabolism of eugenol and methyleugenol has been documented but comparative kinetics have never been conducted in multiple species. Thus, we decided to investigate the bioactivation and detoxification kinetics of eugenol and methyleugenol in human, rat, and mouse to further assess their differential toxicity. The formation of a 1'-hydroxy proximate carcinogen, and a cytotoxic quinone methide, two key toxic metabolites for alkenylbenzenes, were quantified in hepatic and pulmonary microsomes and S9 fractions. Kinetic constants (app)Km, (app)Vmax, and CLint were measured for these reactions. We report that methyleugenol generates a significant amount of the 1'-hydroxy proximate carcinogen while eugenol glucuronidation prevents the formation of both 1'-hydroxyeugenol and the quinone methide. Comparative kinetics highlighted key metabolic differences between human, mouse, and rat, providing a mechanistic insight into the bioactivation and detoxification of alkenylbenzenes in each species.