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The Role of Inosine-5'-Monophosphate Dehydrogenase in Thiopurine Metabolism in Patients With Inflammatory Bowel Disease.

Haglund, Sofie; Vikingsson, Svante; Söderman, Jan; Hindorf, Ulf LU ; Grännö, Christer; Danelius, Margareta; Coulthard, Sally; Peterson, Curt and Almer, Sven (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)
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author
organization
publishing date
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
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
2011-03-01 14:24:21
date last changed
2017-03-26 03:51:50
@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 &gt; 20 (n = 26), in patients with a metabolite ratio ≤20 (n = 21), in a subgroup with a metabolite ratio &lt;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 &gt;20 had lower IMPDH activity than those with ratios ≤20 (P &lt; 0.001). Metabolic ratios &gt;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 &lt; 0.001) but, unexpectedly, also of 6-thioguanosine monophosphate (fold change: 2.6 up to 5.0, P &lt; 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},
  keyword      = {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},
  volume       = {33},
  year         = {2011},
}