Advances in cytochrome P450 molecular biology in veterinary species

Background. The cytochrome P450 (CYP) is a superfamily of heme drug metabolizing enzymes, classified into families and subfamilies according to the identity in amino acid sequences, and involved in the oxidative metabolism of xenobiotics (CYPs 1-3) and relevant endogenous compounds (CYP 4, 11, 17, 19 and 21). Since the beginning of CYP research (late 60s), many progresses have been made. In the 80s, most of CYP-mediated reactions were identified and CYP marker substrates recognized; moreover, genetic, physiological factors as well as drug-drug interactions were shown to affect CYPs expression and activity. In the 90s, with the advent of molecular biology, mechanisms involved in CYP expression, regulation and function were clarified. Hallmarks were the discovery of nuclear receptors (NRs) as well as of microRNAs class of CYP gene expression regulators. In the last decade, “omics” technologies, together with conventional pharmaco-toxicology, provided a huge amount of data about CYPs, particularly useful to understand the individual response to drugs. The veterinary perspective. If CYPs are still extensively studied in humans and laboratory animals, the knowledge in veterinary species is still incomplete and largely based on post-transcriptional approaches. Reasons for such a disparity are the significant species-differences, the lower budget available for fundamental and applied studies and a “cultural” gap between veterinary practice and basic sciences. Nevertheless, the genome release for most of veterinary species (www.ensembl.org) and the abovementioned advances today provide novel tools to study CYPs in veterinary species. Most of studies published so far aimed to: (a) explain in silico some discrepancies in CYPs expression and function; (b) investigate non genetic differences in CYPs and NRs constitutive expression; (c) identify genetic polymorphisms to justify differences in the animal response to xenobiotics; (d) explore the effects of dietary constituents on CYP genes; (e) explain species-differences in CYP regulation; (g) determine relationships between CYPs and productivity traits. Most of studies were made in dog, swine, cattle, chicks and fish species. Besides bioinformatics , molecular techniques mostly used were PCR, immunoblotting and, recently, DNA microarrays and sequencing. Future perspectives. Overall, more fundamental studies are needed to clarify molecular mechanisms governing CYPs expression, regulation and function in veterinary species. Hopefully, new biomolecular tools, e.g. massive parallel sequencing, RNAseq, epigenetics, cell transfection and siRNA, will be more extensively used. This implies an increase of scientific collaborations, an improvement of animal science thinking and, ultimately, the recruitments of researchers with an appreciation of newer and emerging technologies.