Proposed new nomenclature for cattle cytochrome p450 involved in xenobiotic drug metabolism

Introduction. Although the entire bovine genome has recently been sequenced, a definitive nomenclature for cytochromes P450 (CYPs) is still lacking; in fact, cattle CYPs are usually identified with the corresponding human sequence showing the highest percentage of identity, or with the suffix –like [1-2]. Therefore, aim of the present study was to propose a new nomenclature for those cattle CYPs mostly involved, likewise to human and model rodent species, in xenobiotic drug metabolism. Materials and Methods. A phylogenetic analysis of all sequences considered relevant for CYP proteins nomenclature (in particular, CYP families 1-4) and available in GenBank, Ensembl as well as Dr. Nelson’s homepage for CYP nomenclature (http://drnelson.utmem.edu/CytochromeP450.html) databases was made. Final data sets included sequences from most veterinary, primates and laboratory species, fishes, birds as well as species belonging to Insecta, Crustacea and Amphibia, too. Multiple CYPs proteins alignments were made by using the MUSCLE program [3]. Phylogenetic trees were inferred through the maximum likelihood (ML) approach [4]. Models which best fitted data sets were selected using the ProtTest program and according to the Akaike criterion [5]: the evolutionary model that best fitted our multiple alignments was based on Jones et al. substitution matrix (JTT) [6]. Some aligned positions were treated as invariant (I), and the rates of substitution across sites were modeled through a four categories Gamma distribution(G). The best fitting evolutionary model will be henceforth indicated as JTT+I+G. ML phylogenetic analyses were performed by using PHYML 4.4 [7]. Finally, the non parametric bootstrap [8] was run to test the robustness of ML tree topologies. Results. Phylogenetic outputs showed how CYPs sharing the same name and obtained from different species did not form, in several instances, monophyletic groups. With regards to cattle, some CYPs did not group with their supposed orthologous counterparts; thus, a new nomenclature (see Table 1 hereby reported ) was proposed for these proteins. Nomenclature changes were based either on different species orthologous sequences or created ex novo (if no clear orthologous counterparts were identified). As far as CYP3A4 is concerned an alternative acronym (CYP3A28), already available in the SwissProt database, was assigned (see Table 1). Discussion and conclusion. CYP superfamily is one of the most abundant group of genes found in eukaryotic genomes and its nomenclature, even within a single species, is “naturally” complicated by evolutionary mechanisms (i.e., a birth and death process) and gene conversion as well [9-10]. Besides, the adopted naming strategy (based either on time of description or location in the specific genome) contributes to nomenclature problems. The phylogenetic analysis pointed out several inconsistencies between currently used cattle CYPs names and true evolutionary relationships among CYP isoforms. The newly proposed cattle CYPs nomenclature will allow a more appropriate investigation of their biochemical properties and molecular mechanisms, even in veterinary comparative studies on drug metabolism.