Differential Effects of Thiopurine Methyltransferase (TPMT) and Multidrug Resistance-associated Protein Gene 4 (MRP4) on Mercaptopurine Toxicity

Overview

Journal Cancer Chemother Pharmacol

Specialty Oncology

Date 2017 Jun 18

PMID 28623449

Citations 6

Authors

Chengcheng Liu

Laura J Janke

Jun J Yang

William E Evans

John D Schuetz

Mary V Relling

Affiliations

Soon will be listed here.

Abstract

Purpose: Mercaptopurine plays a pivotal role in treatment of acute lymphoblastic leukemia (ALL) and autoimmune diseases, and inter-individual variability in mercaptopurine tolerance can influence treatment outcome. Thiopurine methyltransferase (TPMT) and multi-drug resistant Protein 4 (MRP4) have both been associated with mercaptopurine toxicity in clinical studies, but their relative contributions remain unclear.

Methods: We studied the metabolism of and tolerance to mercaptopurine in murine knockout models of Tpmt, Mrp4, and both genes simultaneously.

Results: Upon mercaptopurine treatment, Tpmt Mrp4 mice had the highest concentration of bone marrow thioguanine nucleotides (8.5 pmol/5 × 10 cells, P = 7.8 × 10 compared with 2.7 pmol/5 × 10 cells in wild-types), followed by those with Mrp4 or Tpmt deficiency alone (6.1 and 4.3 pmol/5 × 10 cells, respectively). Mrp4-deficient mice accumulated higher concentrations of methylmercaptopurine metabolites compared with wild-type (76.5 vs. 23.2 pmol/5 × 10 cells, P = 0.027). Mice exposed to a clinically relevant mercaptopurine dosing regimen displayed differences in toxicity and survival among the genotypes. The double knock-out of both genes experienced greater toxicity and shorter survival compared to the single knockout of either Tpmt (P = 1.7 × 10) or Mrp4 (P = 7.4 × 10).

Conclusions: We showed that both Tpmt and Mrp4 influence mercaptopurine disposition and toxicity.

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