Contribution of –omics methodologies to veterinary pharmacology and toxicology, with special emphasis on drug metabolizing enzymes and drug transporters

Drug metabolizing enzymes (DMEs) and drug transporters (DTs) play a crucial role in determining the kinetics and, eventually, the mechanism of action of drugs, toxins and anthropogenic compounds. Molecular studies about the expression, regulation and biological activity of DMEs/DTs are historically based on the dogma of molecular biology (DNA-mRNA-protein). However, this process is a more complex event. Different mechanisms of regulation contribute to DMEs/DTs gene transcription and translation; moreover, posttranscriptional and posttranslational events may impact on gene expression and ultimately on the amino acid sequence of coded protein (1). In the past two decades, a revolution in the scientific approach to life sciences occurred; researchers moved from studying single genes, mRNAs, proteins or metabolites to studies encompassing entire genomes, transcriptomes, proteomes, and metabolomes. These approaches enabled pharmaco-toxicologists to find new drug targets, identify biomarkers of effect/exposure and unraveling mechanistic relationships (2-4). However, some issues still remain unsolved. Interindividual differences in DMEs/DTs expression and biological activity (pharmacogenetics), as well as other factors like epigenetics, long non-coding RNAs, and gut microbiota, may result in altered drug metabolism and, hence, variations in efficacy, toxicity and adverse reactions (5-7). The aforementioned high-throughput methodologies have also been increasingly used in veterinary sciences, e.g. to identify biomarkers of illicit growth promoters misuse (8), in nutrigenomics (9), in mycotoxins mechanistic toxicology (10), in animal genetics (11). Moreover, an increasing number of papers in which DMEs/DTs were either specifically than indirectly subject of investigation have also been published, including those aiming to identify biomarkers, find non-canonical regulatory pathways, estimate the consequences of altered gene expression, and discover pathways beyond drug metabolism involved in mechanistic pharmaco-toxicology (12-18). In conclusion, omics tools can accelerate our understanding of gene/protein/metabolite networks resulting from the exposure of veterinary species to xenobiotics. Likewise to humans, these techniques may contribute to a better understanding of interindividual and species-differences in DMEs/DTs transcriptional regulation and, consequently, in kinetics, susceptibility and response to xenobiotics. References (1) Glubb and Innocenti. Wiley Interdiscip Rev Syst Biol Med 2011; 3: 299-313. (2) Kaddurah-Daouk et al. Clin Pharmacol Ther 2015; 98: 71-75. (3) Dellafiora and Dall’Asta. Toxins 2017; 9: 18. (4) Joseph et al. J Appl Toxicol 2013; 33: 1193–1202. (5) Ahmed et al. Genomics Proteomics Bioinformatics 2016;14: 298-313. (6) Huang et al. J Appl Toxicol 2018; doi: 10.1002/jat.3595. (7) Yu et al. Acta Pharm Sin B 2017; 7:241-248. (8) Riedmaier et al. Anal Chem 2012; 84: 6863-6868. (9) Osorio et al. Small Ruminant Res 2017; 154: 29-44. (10) Wang et al. Mol Cell Proteomics 2011; 10: M111.008748. (11) Wickramasinghe et al. Livest Sci 2014; 166: 206-216. (12) Craft et al. J Vet Intern Med 2017; 31:1833–1840. (13) Giantin et al. Vet J 2016; 212: 36-43. (14) Heikkinen et al. Pharm Res 2015; 32: 74–90. (15) Howard et al. Sci Rep 2017; 7: 1357. (16) Li et al. In Vitro Cell Dev Biol - Animal 2017; 53: 293-303. (17) Reddy et al. Asian-Australas J Anim Sci 2018; 31: 138-148. (18) Visser et al. J Vet Pharmacol Ther 2017; 40: 583-590.