The Role of Inosine-5'-Monophosphate Dehydrogenase in Thiopurine Metabolism in Patients With Inflammatory Bowel Disease.
(2011) In Therapeutic Drug Monitoring 33(2). p.200-208- Abstract
- BACKGROUND:: There is a large interindividual variability in thiopurine metabolism. High concentrations of methylthioinosine-5'-monophosphate (meTIMP) and low concentrations of 6-thioguanine nucleotides (6-TGNs) have been associated with a lower response rate and an increased risk of adverse events. In this study, the role of inosine-5'-monophosphate dehydrogenase (IMPDH) for differences in metabolite patterns of thiopurines was investigated. METHODS:: IMPDH activity and thiopurine metabolite concentrations were determined in patients with inflammatory bowel disease and a normal thiopurine methyltransferase (TPMT) phenotype and meTIMP/6-TGN concentration ratio > 20 (n = 26), in patients with a metabolite ratio ≤20 (n = 21), in a... (More)
- BACKGROUND:: There is a large interindividual variability in thiopurine metabolism. High concentrations of methylthioinosine-5'-monophosphate (meTIMP) and low concentrations of 6-thioguanine nucleotides (6-TGNs) have been associated with a lower response rate and an increased risk of adverse events. In this study, the role of inosine-5'-monophosphate dehydrogenase (IMPDH) for differences in metabolite patterns of thiopurines was investigated. METHODS:: IMPDH activity and thiopurine metabolite concentrations were determined in patients with inflammatory bowel disease and a normal thiopurine methyltransferase (TPMT) phenotype and meTIMP/6-TGN concentration ratio > 20 (n = 26), in patients with a metabolite ratio ≤20 (n = 21), in a subgroup with a metabolite ratio <4 (n = 6), and in 10 patients with reduced TPMT activity. In vitro studies were conducted on human embryonic kidney cells (HEK293) with genetically engineered IMPDH and TPMT activities. RESULTS:: Patients with metabolite ratios >20 had lower IMPDH activity than those with ratios ≤20 (P < 0.001). Metabolic ratios >20 were only observed in patients with normal TPMT activity. Downregulation of IMPDH activity in HEK293 cells was associated with an increase in the concentration of meTIMP (fold change: 17 up to 93, P < 0.001) but, unexpectedly, also of 6-thioguanosine monophosphate (fold change: 2.6 up to 5.0, P < 0.001). CONCLUSIONS:: These data question the general view of IMPDH as the rate-limiting enzyme in the phosphorylation of thiopurines. Investigations of other mechanisms are needed to more fully explain the various metabolite patterns and outcomes in patients under treatment. (Less)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/1831964
- author
- Haglund, Sofie ; Vikingsson, Svante ; Söderman, Jan ; Hindorf, Ulf LU ; Grännö, Christer ; Danelius, Margareta ; Coulthard, Sally ; Peterson, Curt and Almer, Sven
- organization
- publishing date
- 2011
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- IMPDH, inosine-5-monophosphate dehydrogenase, 6-TGN, meTIMP, thiopurines, therapeutic drug monitoring
- in
- Therapeutic Drug Monitoring
- volume
- 33
- issue
- 2
- pages
- 200 - 208
- publisher
- Lippincott Williams & Wilkins
- external identifiers
-
- wos:000288498100010
- pmid:21311411
- scopus:79953230029
- pmid:21311411
- ISSN
- 0163-4356
- DOI
- 10.1097/FTD.0b013e31820b42bb
- language
- English
- LU publication?
- yes
- id
- 88848b0f-4201-430f-b075-a69d12db6738 (old id 1831964)
- alternative location
- http://www.ncbi.nlm.nih.gov/pubmed/21311411?dopt=Abstract
- date added to LUP
- 2016-04-01 13:32:04
- date last changed
- 2024-01-24 11:32:41
@article{88848b0f-4201-430f-b075-a69d12db6738,
abstract = {{BACKGROUND:: There is a large interindividual variability in thiopurine metabolism. High concentrations of methylthioinosine-5'-monophosphate (meTIMP) and low concentrations of 6-thioguanine nucleotides (6-TGNs) have been associated with a lower response rate and an increased risk of adverse events. In this study, the role of inosine-5'-monophosphate dehydrogenase (IMPDH) for differences in metabolite patterns of thiopurines was investigated. METHODS:: IMPDH activity and thiopurine metabolite concentrations were determined in patients with inflammatory bowel disease and a normal thiopurine methyltransferase (TPMT) phenotype and meTIMP/6-TGN concentration ratio > 20 (n = 26), in patients with a metabolite ratio ≤20 (n = 21), in a subgroup with a metabolite ratio <4 (n = 6), and in 10 patients with reduced TPMT activity. In vitro studies were conducted on human embryonic kidney cells (HEK293) with genetically engineered IMPDH and TPMT activities. RESULTS:: Patients with metabolite ratios >20 had lower IMPDH activity than those with ratios ≤20 (P < 0.001). Metabolic ratios >20 were only observed in patients with normal TPMT activity. Downregulation of IMPDH activity in HEK293 cells was associated with an increase in the concentration of meTIMP (fold change: 17 up to 93, P < 0.001) but, unexpectedly, also of 6-thioguanosine monophosphate (fold change: 2.6 up to 5.0, P < 0.001). CONCLUSIONS:: These data question the general view of IMPDH as the rate-limiting enzyme in the phosphorylation of thiopurines. Investigations of other mechanisms are needed to more fully explain the various metabolite patterns and outcomes in patients under treatment.}},
author = {{Haglund, Sofie and Vikingsson, Svante and Söderman, Jan and Hindorf, Ulf and Grännö, Christer and Danelius, Margareta and Coulthard, Sally and Peterson, Curt and Almer, Sven}},
issn = {{0163-4356}},
keywords = {{IMPDH; inosine-5-monophosphate dehydrogenase; 6-TGN; meTIMP; thiopurines; therapeutic drug monitoring}},
language = {{eng}},
number = {{2}},
pages = {{200--208}},
publisher = {{Lippincott Williams & Wilkins}},
series = {{Therapeutic Drug Monitoring}},
title = {{The Role of Inosine-5'-Monophosphate Dehydrogenase in Thiopurine Metabolism in Patients With Inflammatory Bowel Disease.}},
url = {{http://dx.doi.org/10.1097/FTD.0b013e31820b42bb}},
doi = {{10.1097/FTD.0b013e31820b42bb}},
volume = {{33}},
year = {{2011}},
}