Defective TPMT causes TPMT deficiency

Stable Identifier
R-HSA-5578995
Type
Pathway
Species
Homo sapiens
Synonyms
Defective TPMT causes Thiopurine S-methyltransferase deficiency (TPMT deficiency)
ReviewStatus
5/5
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Defective TPMT causes TPMT deficiency
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Methylation is a major biotransformation route of thiopurine drugs such as 6-mercaptopurine (6MP), used in the treatment of inflammatory diseases such as rheumatoid arthritis and childhood acute lymphoblastic leukemia. 6MP and its thioguanine nucleotide metabolites are principally inactivated by thiopurine methyltransferase (TPMT)-catalysed S-methylation.

Defects in TPMT can cause thiopurine S-methyltransferase deficiency (TPMT deficiency; MIM:610460). Patients with intermediate or no TPMT activity are at risk of toxicity such as myelosuppression after receiving standard doses of thiopurine drugs. Inter individual differences in response to these drugs are largely determined by genetic variation at the TPMT locus. TPMT exhibits an autosomal co dominant phenotype: About one in 300 people in Caucasian, African, African-American, and Asian populations are TPMT deficient. Approximately 6-10% of people in these populations inherit intermediate TPMT activity and are heterozygous at the TPMT locus. The rest are homozygous for the wild type allele and have high levels of TPMT activity. (Remy 1963, Weinshilboum et al. 1999, Couldhard & Hogarth 2005, Al Hadithy et al. 2005, Azimi et al. 2014).
Literature References
PubMed ID Title Journal Year
24734162 Assessment of Thiopurine-based drugs according to Thiopurine S-methyltransferase genotype in patients with Acute Lymphoblastic Leukemia

Azimi, F, Jafariyan, M, Khatami, S, Mortazavi, Y, Azad, M

Iran J Ped Hematol Oncol 2014
13981612 Metabolism of thiopyrimidines and thiopurines. S-Methylation with S-adenosylmethionine transmethylase and catabolism in mammalian tissues.

Remy, CN

J Biol Chem 1963
16267626 The thiopurines: an update

Coulthard, S, Hogarth, L

Invest New Drugs 2005
15788214 Thiopurines in inflammatory bowel disease: pharmacogenetics, therapeutic drug monitoring and clinical recommendations

Al Hadithy, AF, de Boer, NK, Derijks, LJ, Escher, JC, Mulder, CJ, Brouwers, JR

Dig Liver Dis 2005
10331075 Methylation pharmacogenetics: catechol O-methyltransferase, thiopurine methyltransferase, and histamine N-methyltransferase

Weinshilboum, RM, Otterness, DM, Szumlanski, CL

Annu Rev Pharmacol Toxicol 1999
Participants
Events
Participates
as an event of
Disease
Name Identifier Synonyms
inherited metabolic disorder DOID:655 Metabolic hereditary disorder, Inborn Errors of Metabolism, inborn metabolism disorder
Cross References
Mondo
Authored
Jassal, B  (2014-06-06)
Reviewed
Nakaki, T  (2014-11-03)
Created
Jassal, B  (2014-06-06)
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