Cat Red Blood Cell ThiopurineS-Methyltransferase: Companion Animal Pharmacogenetics

Abstract

A common genetic polymorphism for thiopurine S-methyltransferase (TPMT) is a major factor responsible for individual variation in the toxicity and therapeutic efficacy of thiopurine drugs in humans. We set out to determine whether inheritance might also influence the level of TPMT activity in the domestic cat, Felis domesticus. As a first step, red blood cell (RBC) TPMT activity was measured in blood samples from 104 cats. The average level of cat RBC TPMT activity was lower than that observed in humans and was not related to either age or sex of the animal. We then cloned and characterized the F. domesticus TPMT cDNA and gene. Genotype-phenotype correlation analysis was performed by resequencing the cat TPMT gene using DNA samples from 12 animals with high and 12 with low levels of RBC TPMT activity. Thirty-one single nucleotide polymorphisms (SNPs) were observed in these 24 DNA samples, including five that altered the encoded amino acid, resulting in nine allozymes (six observed and three inferred). Twelve of the 31 feline TPMT SNPs were associated, collectively, with 56% of the variation in level of RBC TPMT activity in these 24 animals. When those 12 SNPs were assayed in all 89 cats for which DNA was available, 30% of the variation in level of RBC TPMT activity was associated with these 12 polymorphisms. After expression in COS-1 cells, five of the eight variant cat allozymes displayed decreased levels of both TPMT activity and immunoreactive protein compared with the wild-type allozyme. These observations are compatible with the conclusion that inheritance is an important factor responsible for variation in levels of RBC TPMT activity in the cat. They also represent a step toward the application of pharmacogenetic principles to companion animal thiopurine drug therapy.

Identification of the novel canine CYP1A2 1117 C>T SNP causing protein deletion

“…Although mammalian cross-species genome structures are generally different, the length of the internal exon encoded proteins is the same (Salavaggione et al 2002). Based on the similarity of the mammalian CYP1A subfamily, the 1117 C>T SNP is predicted to be located in exon 4 of canine CYP1A2.…”

Impact of Chemotherapeutic Dose Intensity and Hematologic Toxicity on First Remission Duration in Dogs with Lymphoma Treated with a Chemoradiotherapy Protocol

“…Drug disposition, MDR1 status, and other pharmacokinetic markers could be assessed in individual dogs in an attempt to elucidate the mechanism or mechanisms behind our findings. 50,54 Such studies eventually may allow drug doses to be tailored to the pharmacogenomic profile of an individual patient, which theoretically would provide a dependable predictive tool for ensuring that cytotoxic treatments are given both effectively and safely from the onset of therapy. …”

Pharmacogenetic and Metabolic Differences Between Dog Breeds: Their Impact on Canine Medicine and the Use of the Dog as a Preclinical Animal Model

“…A list of identified breed-specific idiosyncrasies that can influence drug absorption and metabolism are provided in Tables III and IV ( [40][41][42][43][44][45][46][47][48][49][50][51][52][53][54]. Table III includes recognized metabolic idiosyncrasies and Table IV includes physiologic idiosyncrasies.…”