title: The role of inosine-5'-monophosphate dehydrogenase in thiopurine metabolism in patients with inflammatory bowel disease.
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). Metabolite 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.
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Experimental and Clinical Medicine, Linköping University, Linköping, Sweden. sofie.haglund@lj.se
authors.forename: Sofie
authors.initials: S
authors.lastname: Haglund
authors.forename: Svante
authors.initials: S
authors.lastname: Vikingsson
authors.forename: Jan
authors.initials: J
authors.lastname: Söderman
authors.forename: Ulf
authors.initials: U
authors.lastname: Hindorf
authors.forename: Christer
authors.initials: C
authors.lastname: Grännö
authors.forename: Margareta
authors.initials: M
authors.lastname: Danelius
authors.forename: Sally
authors.initials: S
authors.lastname: Coulthard
authors.forename: Curt
authors.initials: C
authors.lastname: Peterson
authors.forename: Sven
authors.initials: S
authors.lastname: Almer
mesh_terms: D000293:Adolescent; D000305:Adrenal Cortex Hormones / Q000008:administration & dosage / Q000378:metabolism; D000328:Adult; D000368:Aged; D000636:Aminosalicylic Acids / Q000008:administration & dosage / Q000378:metabolism; D002648:Child; D005260:Female; D006150:Guanine Nucleotides / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D007168:IMP Dehydrogenase / Q000235:genetics* / Q000378:metabolism*; D015212:Inflammatory Bowel Diseases / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics; D008297:Male; D008780:Methyltransferases / Q000235:genetics* / Q000378:metabolism*; D008875:Middle Aged; D010641:Phenotype; D010766:Phosphorylation; D012333:RNA, Messenger / Q000096:biosynthesis; D013868:Thioinosine / Q000031:analogs & derivatives* / Q000378:metabolism; D013873:Thionucleotides / Q000378:metabolism*; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000305:Adrenal Cortex Hormones; D000636:Aminosalicylic Acids; D006150:Guanine Nucleotides; D012333:RNA, Messenger; D013873:Thionucleotides; C003964:6-thioguanylic acid; D013868:Thioinosine; C002344:6-methylthiopurine ribonucleoside-5'-phosphate; D007168:IMP Dehydrogenase; D008780:Methyltransferases; C022745:thiopurine methyltransferase