Pharmacogenetics of cytochrome P450 in veterinary species: an update.

Recent advances in genetics have spurred growth in research linking genetics and pharmacology. Pharmacogenetics focuses on genetic causes of individual variations in drug response, while pharmacogenomics is the genome-wide analysis of genetic determinants of drug efficacy and toxicity. Historically, human pharmacogenomics began as early as the 1950s, with observed differences in drug response and toxicity in racial/ethnic groups. The majority of phase I drug-metabolizing enzymes, and mostly cytochromes P450 (CYPs), are known to be polymorphic; therefore, studying CYP genetic polymorphisms is of great importance to understand the variability in responses to xenobiotics. By comparison, veterinary pharmacogenetics is relatively still underdeveloped. Above and beyond a gap between veterinary and life sciences researchers and the minor amount of funds available for fundamental and applied research, other genetic (species, breed, sex) and dynamic non-genetic factors (age, induction/inhibition phenomena, health-related conditions, diet), have historically been attributed major importance. To the best of our knowledge, only four reviews describing CYP genetic polymorphisms in species of veterinary interest have been published so far, and most of data concern canine CYPs. In this species, the prevalence of a known CYP1A2 stop codon seems to vary considerably between and within dog breeds. Similarly, breed has been proved as a key genetic factor affecting CYP expression and function in food-producing species, e.g. cattle, chicken, horse and pigs. Actually, the genome sequencing and analysis projects and the advances in high-throughput genotyping and DNA sequencing have dramatically changed the approach to CYP pharmacogenetics and pharmacogenomics. This has been recently proved also in cattle (CYP3A) and pigs (CYP2E1). Furthermore, this genome-wide approach has also uncovered novel genes and genetic variants (i.e., nuclear receptors, contributing to CYP regulation) as well as new biological pathways influencing not only drug metabolism/response (i.e., productivity traits). In conclusion, CYP genetic polymorphisms have been associated with differences in drug metabolism and/or response and productivity traits in veterinary species. Further studies are needed to characterize the expression, the transcriptional activity and post-translational effects of these and other related genetic polymorphisms.