Phylogenetic analysis of the cytochrome P450 (CYP450) nucleotide sequences of the horse and predicted CYP450s of the white rhinoceros (Ceratotherium simum) and other mammalian species

Abstract

BackgroundThe plight of the white rhinoceros (Ceratotherium simum) and the increasing need of treatment options for injured poaching victims led to the necessity to expand the knowledge on applicable drugs in this endangered species. With very little information available on drug pharmacokinetics in rhino, veterinarians have to rely on information generated from other species. The horse being a closely related species, has served as the model for dose extrapolations. However, from recent research on enrofloxacin and carprofen, the white rhino showed considerable differences in the pharmacokinetic properties of these drugs in comparison to the horse. While the reason for the differences is unknown, a likely cause may be a difference in present cytochrome P450 (CYP450), which may result in the rhino being genetically deficient in certain enzyme families.MethodsFor this paper we assess the degree of similarity of the CYP genome sequences across the different species, using BLAT (BLAST-like alignment tool) for the alignment of the nucleotide sequences of the equine CYP450 with potential homologous nucleotide sequences of the published database from white rhinos and other mammalian species (cow, pig, dog, sheep, elephant, mouse and human).ResultsThe white rhino nucleotide sequences were 90.74% identical to the equine sequences. This was higher than the degree of similarity between any of the other evaluated species sequences. While no specific CYP family were found to be deficient in the published rhino genome, the horse genome contained additional genetic sequence for a larger number of iso-enzymes that were not present in the rhino.DiscussionIn pharmacokinetic study, it is well known that absence of a metabolic enzyme will result in constraints in drug metabolism and drug elimination. While this was our speculation, comparison to the horse and other mammalian species indicate that all the described CYP genes required for metabolism are present within the rhino genome. These results leave functional differences in enzyme activity and a lack of isoenzymes as the likely reason for the constraint in drug metabolism. Despite a more than 90% similarity of the equine and rhino gene sequences, seemingly small differences can have major effects on drug metabolism. Thus, in spite of the close anatomical relationship, the rhino should not simply be treated like a big horse.

Sequencing of the Canine Cytochrome P450 CYP2C41 Gene and Genotyping of Its Polymorphic Occurrence in 36 Dog Breeds

“…Among all CYPs involved in hepatic drug metabolism, the subfamily CYP2C is of particular interest in the context of canine-to-human comparison, as notable species differences exist in the CYP2C subfamily. At present, four CYP2C genes have been identified in humans ( 21 ), five in rats ( 22 ), 15 in mice ( 23 ), two in cats ( 24 ), and two in horses ( 25 ). Genetic polymorphisms in CYP2C genes have been shown to be of clinical relevance in humans ( 26 ).…”

Pharmacokinetics of intravenous propofol in southern white rhinoceros (Ceratotherium simum simum) after intramuscular etorphine-butorphanol-medetomidine-azaperone

“…The reasons are not known, but a difference in the CYP450 enzyme genome, an important enzyme for propofol metabolism, may explain the differences in the metabolism of drugs. 25,26 While the logistics and risks of anesthetizing mega-vertebrates result in inherent limitations, this study was unique in that authors were able to perform the same procedure on 5 rhinoceros in a controlled setting with the same initial drug protocol, reducing aspects of variability between animals. Due to logistical considerations, a blood sample prior to drug administration could not be obtained.…”

Phenylbutazone pharmacokinetics in southern white rhinoceros (Ceratotherium simum simum) after oral administration

“…For example, horses and SWR have very different elimination curves for carprofen with a T 1/2 of 21.9 and 106 h, respectively (Leiberich, Krebber, et al, 2018). Despite a similar gastrointestinal tract and having the same cytochrome P450 family genomes present, horses possess a greater number of sequences for iso‐enzymes than SWR, which may cause differences in drug elimination between these two species (Leiberich et al, 2018).…”