Xenobiotic metabolomics: major impact on the metabolome

Abstract

Xenobiotics are encountered by humans on a daily basis and include drugs, environmental pollutants, cosmetics, and even components of the diet. These chemicals undergo metabolism and detoxication to produce numerous metabolites, some of which have the potential to cause unintended effects such as toxicity. They can also block the action of enzymes or receptors used for endogenous metabolism or affect the efficacy and/or bioavailability of a coadministered drug. Therefore, it is essential to determine the full metabolic effects that these chemicals have on the body. Metabolomics, the comprehensive analysis of small molecules in a biofluid, can reveal biologically relevant perturbations that result from xenobiotic exposure. This review discusses the impact that genetic, environmental, and gut microflora variation has on the metabolome, and how these variables may interact, positively and negatively, with xenobiotic metabolism.

Figure 1

Interindividual genomic, environmental, and gut microflora variation can contribute to an individual-specific metabotype or metabolomic fingerprint. Each of these factors can influence the others and determine the outcome of the metabotype. Conversely, the individual’s metabolome can affect each one of the factors.

Figure 2

Metabolic reactions of (a) cyclophosphamide and (b) ifosfamide in mouse urine. Boxed structures in pink represent proposed reactive metabolites; boxed structures in blue represent novel metabolites discovered by UPLC-ESI-QTOFMS-based metabolomics (i.e., metabolomics based on ultraperformance liquid chromatography–electrospray ionization–quadrupole time-of-flight mass spectrometry). Abbreviation: GSH, glutathione.

Figure 2

Metabolic reactions of (a) cyclophosphamide and (b) ifosfamide in mouse urine. Boxed structures in pink represent proposed reactive metabolites; boxed structures in blue represent novel metabolites discovered by UPLC-ESI-QTOFMS-based metabolomics (i.e., metabolomics based on ultraperformance liquid chromatography–electrospray ionization–quadrupole time-of-flight mass spectrometry). Abbreviation: GSH, glutathione.

Figure 3

Proposed metabolism of fenofibrate after ultraperformance liquid chromatography-electrospray ionization-quadrupole time-of-flight mass spectrometry (UPLC-ESI-QTOFMS)-based metabolomics analysis of dosed cynomolgus monkeys and rats. Items highlighted in blue are novel metabolites.