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Keywords:

  • 6-mercaptopurine;
  • azathioprine;
  • IMPDH;
  • inflammatory bowel disease;
  • inosine-5′-monophosphate dehydrogenase;
  • thiopurine

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• Up to 30% of inflammatory bowel disease patients treated with the thiopurine drugs azathioprine and 6-mercaptopurine do not respond properly to therapy.

• Genetic variation in the polymorphic enzyme thiopurine S-methyltransferase (TPMT) is associated with adverse events if patients are treated with standard doses.

• However, not all adverse events or metabolite patterns can be explained by genetic variations in TPMT, therefore we investigated the role of another thiopurine-metabolizing enzyme, inosine-5′-monophosphate dehydrogenase (IMPDH).

WHAT THIS STUDY ADDS

• There was a negative correlation of mononuclear cell (MNC) IMPDH activity with red blood cell (RBC) 6-methylthioinosine 5′-monophosphate, but not with RBC 6-thioguanine nucleotide (6-TGN).

• The results indicate either that measuring thiopurine metabolites in RBC, as is the current practice in clinical monitoring, is not an appropriate surrogate compartment for MNC metabolite concentrations, or that IMPDH in MNC is not as important a rate-limiting enzyme in the interconversion of thioinosine monophosphate to 6-TGN as has been hypothesized.

• All metabolite concentrations and enzymatic activities should preferably be measured in the same compartment.

AIMS

Azathioprine and 6-mercaptopurine are steroid-sparing drugs used in inflammatory bowel disease (IBD). The polymorphic enzyme thiopurine S-methyltransferase (TPMT) is of importance for thiopurine metabolism and occurrence of adverse events. The role of other thiopurine-metabolizing enzymes is less well known. This study investigated the role of inosine-5′-monophosphate dehydrogenase (IMPDH), which is a key enzyme in the de novo synthesis of guanine nucleotides and also strategically positioned in the metabolic pathway of thiopurines.

METHODS

IMPDH was measured in 100 healthy blood donors. IMPDH, TPMT and metabolite concentrations were studied in 50 patients with IBD on stable thiopurine therapy. IMPDH activity was measured in peripheral blood mononuclear cells. TPMT activity, 6-methylthioinosine 5′-monophosphate (meTIMP) and 6-thioguanine nucleotide (6-TGN) concentrations were measured in red blod cells, which is the current practice in clinical monitoring of thiopurines. Enzyme activities were related to metabolite concentrations and clinical characteristics.

RESULTS

A wide range of IMPDH activity was observed both in healthy blood donors (median 13.1, range 4.7–24.2 nmol mg−1 protein h−1) and IBD patients (median 14.0, range 7.0–21.7). There was a negative correlation between IMPDH activity and dose-normalized meTIMP concentrations (rs = −0.31, P = 0.03), but no evident correlation to 6-TGN concentration or the meTIMP/6-TGN ratio. There were no significant correlations between TPMT activity and metabolite concentrations.

CONCLUSION

Even though the meTIMP concentrations correlated inversely to the IMPDH activity, the role of IMPDH in balancing the formation of methylated and phosphorylated metabolites was not evident. Taken together, the results give cause to question established opinions about thiopurine metabolism.