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The Role of Inosine...
The Role of Inosine-5'-Monophosphate Dehydrogenase in Thiopurine Metabolism in Patients With Inflammatory Bowel Disease.
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- Haglund, Sofie (författare)
- Linköpings universitet,Gastroenterologi och hepatologi,Hälsouniversitetet
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- Vikingsson, Svante (författare)
- Linköpings universitet,Klinisk farmakologi,Hälsouniversitetet
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- Söderman, Jan (författare)
- Division of Medical Diagnostics, Laboratory Medicine, Ryhov Hospital, Jönköping;
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- Hindorf, Ulf (författare)
- Lund University,Lunds universitet,Medicin, Lund,Sektion II,Institutionen för kliniska vetenskaper, Lund,Medicinska fakulteten,Medicine, Lund,Section II,Department of Clinical Sciences, Lund,Faculty of Medicine,Department of Gastroenterology, Lund University Hospital, Lund
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- Grännö, Christer (författare)
- Department of Medicine, Ryhov Hospital, Jönköping
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- Danelius, Margareta (författare)
- Department of Internal Medicine, Ersta Hospital, Stockholm, Sweden
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- Coulthard, Sally (författare)
- Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, United Kingdom
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- Peterson, Curt (författare)
- Östergötlands Läns Landsting,Linköpings universitet,Klinisk farmakologi,Hälsouniversitetet,Onkologiska kliniken US
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- Almer, Sven (författare)
- Östergötlands Läns Landsting,Linköpings universitet,Gastroenterologi och hepatologi,Hälsouniversitetet,Endokrin- och magtarmmedicinska kliniken US
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(creator_code:org_t)
- Lippincott Williams & Wilkins, 2011
- 2011
- Engelska.
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Ingår i: Therapeutic Drug Monitoring. - : Lippincott Williams & Wilkins. - 0163-4356 .- 1536-3694. ; 33:2, s. 200-208
- Relaterad länk:
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http://www.ncbi.nlm....
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http://dx.doi.org/10...
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https://lup.lub.lu.s...
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https://doi.org/10.1...
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https://urn.kb.se/re...
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Abstract
Ämnesord
Stäng
- 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.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Annan klinisk medicin (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Other Clinical Medicine (hsv//eng)
Nyckelord
- IMPDH
- inosine-5-monophosphate dehydrogenase
- 6-TGN
- meTIMP
- thiopurines
- therapeutic drug monitoring
- MEDICINE
Publikations- och innehållstyp
- art (ämneskategori)
- ref (ämneskategori)
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