Thiopurine Methyltransferase in Red Blood Cells of Dogs, Cats, and Horses

White, Stephen D.; Rosychuk, Rod A.W.; Outerbridge, Catherine A.; Fieseler, Kathryn V.; Spier, Sharon J.; Ihrke, Peter J.; Chapman, Phillip L.

doi:10.1111/j.1939-1676.2000.tb02266.x

Cited by 27 publications

(15 citation statements)

References 23 publications

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“…Two previous studies that included a much smaller number of cats also reported that levels of RBC TPMT activity in this species were only approximately one-fifth of those observed in humans or dogs (Foster et al, 2000;White et al, 2000). If RBC TPMT activity reflects the level of this enzyme activity in other cat tissues, these relatively low levels of activity may help to explain the sensitivity of this species to thiopurine therapy (Beale et al, 1992).…”

Section: Discussionmentioning

confidence: 88%

“…The thiopurine drugs that are metabolized by TPMT are also used to treat companion animals, including cats, and companion animals also display large individual variations in thiopurine efficacy and toxicity (Houston and Taylor, 1991;Rinkhardt and Kruth, 1996). Cats in particular have been reported to be especially sensitive to myelosuppression after azathioprine therapy (Beale et al, 1992), and some authors have even recommended that these drugs not be used to treat cats (White et al, 2000). If principles of individualized therapy based, in part, on pharmacogenetics are of value when applied to humans, it is reasonable to ask whether similar principles might also apply to companion animals.…”

Section: Discussionmentioning

confidence: 99%

“…Thiopurine drugs such as 6-mercaptopurine (6-MP) and azathioprine, which is converted to 6-MP in vivo, are used to treat both humans and companion animals, including the domestic cat, Felis domesticus (Paterson and Tidd, 1975;Lennard, 1992;White et al, 2000). In humans, these drugs are used as cytotoxic agents to treat neoplasia and as immune suppressants (Paterson and Tidd, 1975;Lennard, 1992), with a similar spectrum of therapeutic applications in companion animals (Beale, 1988).…”

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confidence: 99%

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Cat Red Blood Cell ThiopurineS-Methyltransferase: Companion Animal Pharmacogenetics

Salavaggione¹,

Yang²,

Kidd³

et al. 2003

J Pharmacol Exp Ther

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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.

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Section: Discussionmentioning

confidence: 88%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Cat Red Blood Cell ThiopurineS-Methyltransferase: Companion Animal Pharmacogenetics

Salavaggione¹,

Yang²,

Kidd³

et al. 2003

J Pharmacol Exp Ther

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“…The drugs were slowly tapered and discontinued, and the horse has not relapsed. In humans and rodents azathioprine is metabolized in the liver (and possibly other organs) by thiopurine methyltransferase (TPMT) an enzyme detectable in human lysed red blood cells (RBC) 36,37 . When the TPMT RBC enzyme level was measured in dogs, cats and horses, it was found that the level was highest in dogs, lower in cats and lowest in horses 38 .…”

Section: Discussionmentioning

confidence: 99%

Pemphigus foliaceus in the horse: a retrospective study of 20 cases

Vandenabeele

White²,

Affolter

et al. 2004

Veterinary Dermatology

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Twenty horses with pemphigus foliaceus were seen over a period of 15 years in a veterinary medical teaching hospital. Breeds seen were seven quarterhorses, five thoroughbreds, three cross-bred horses, two Arabians and one of each of the following: standardbred, Tennessee walker and warmblood. There was no breed, age or sex predisposition. Nine were mares, ten were geldings and one was a stallion. Ages ranged from 2.5 months to 25 years, with a mean of 8.6 years. Sixteen (80%) of the pemphigus foliaceus horses first exhibited signs between September and February. There was a statistically significant more common occurrence of pemphigus foliaceus during those months. Signs in the four other horses were first noted in March, May or June. Three of those horses were < 13 months of age. Oedema (14/20) and crusts (13/20) were the most common lesions. Pain was present in 9/20 horses, pruritus in 7/20 and pyrexia in 7/20. Follow-up was available for 13 horses. Five of these horses were euthanased. In three horses the reason for euthanasia was laminitis secondary to treatment. Four horses remained lesion-free after medication was discontinued. Two horses required maintenance medication and are doing well at the time of writing.

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“…The use of azathioprine in cats is reportedly associated with a life-threatening leukopenia and thrombocytopenia (Beale 1990, Beale et al 1992, Plumb 1999, Scott et al 2001, that could be attributed to the low erythrocyte thiopurine methyltransferase activity in this animal species (Foster et al 2000, Papich 2000, White et al 2000. Lower doses of azathioprine, such as 0.3 mg/kg BW, once daily (Papich 2000), 0.3-0.5 mg/kg BW every 48 hours (Birchard and Sherding 2000) or 1.5-3.125 mg/cat every 48 hours (Papich 1995), are thought to be relatively safer.…”

Section: Discussionmentioning

confidence: 99%

A case of periosteal proliferative polyarthritis in a cat

Karayannopoulou¹,

Polizopoulou²,

Koutinas

et al. 2017

J Hellenic Vet Med Soc

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In this paper a case of periosteal proliferative polyarthritis in an 11-year old, female Siamese cat, that was admitted to the Surgery Clinic of the Veterinary School, A.U.Th., with a 6-month history of non-weight bearing lameness of the left thoracic limb, is described. At physical examination, restricted range of motion of the left elbow joint, local swelling and pain were detected. In the radiological examination of the affected joint the main finding was a periarticular extensive and irregular periosteal new bone formation. The results of the complete blood count and routine serum biochemistry were within normal limits and the cat was serologically negative for FeLV and FIV. Synovial fluid examination showed a lymphoplasmacytic pleocytosis, while the bacterial culture was negative. Prednisolone given at an anti-inflammatory dose for two consecutive weeks resulted in a marked improvement of the clinical sings. However, two months after the end of the treatment lameness reappeared, but this time in the contralateral thoracic limb, due to the involvement of the same joint. Radiology revealed the same type of lesions in the right elbow joint, whereas the left became ankylosed. Again, prednisolone, given at an immunosuppressive dose for two weeks, did not improve but fairly the clinical condition of the animal and the radiological changes as well. For this reason azathioprine at the dose of 1 mg/kg BW, every 48 hours, was added to therapy that lasted for 5 months. Transient mild leukopenia, that resolved after decreasing the dose of azathioprine by 25%, was the only adverse side effect noticed. At the end of the treatment, regression of the radiographical lesions in both elbows enabled the cat to walk with a stilted gait, despite the development of joint ankylosis bilaterally. The disease was kept in remission during the 12-month follow up period.

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Thiopurine Methyltransferase in Red Blood Cells of Dogs, Cats, and Horses

Cited by 27 publications

References 23 publications

Cat Red Blood Cell ThiopurineS-Methyltransferase: Companion Animal Pharmacogenetics

Cat Red Blood Cell ThiopurineS-Methyltransferase: Companion Animal Pharmacogenetics

Pemphigus foliaceus in the horse: a retrospective study of 20 cases

A case of periosteal proliferative polyarthritis in a cat

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