The multidrug-resistance protein 4 polymorphism is a new factor accounting for thiopurine sensitivity in Japanese patients with inflammatory bowel disease

J Gastroenterol. 2010 Oct;45(10):1014-21. doi: 10.1007/s00535-010-0248-y.


Background: Multidrug resistance protein 4 (MRP4) functions as an efflux pump of nucleoside monophosphate analogs, such as 6-mercaptopurine (6-MP) and 6-thioguanine nucleotide (6-TGN). A single-nucleotide polymorphism in human MRP4 (rs3765534) dramatically reduces MRP4 function and results in the intracellular accumulation of 6-TGN. In this study, we investigated the association between MRP4 G2269A polymorphism and thiopurine sensitivity in Japanese IBD patients.

Methods: Direct sequencing of the MRP4 exon 18 was performed. The TPMT A719G and ITPase C94A polymorphisms were determined by polymerase-chain reaction-restriction fragment length polymorphism analyses.

Results: Of the 279 samples analyzed (44 healthy volunteers and 235 IBD patients), 68 samples showed a heterozygote of MRP4 G2269A and 7 carried a homozygote. The allelic frequency of MRP4 G2269A was 14.7%. In 130 IBD patients treated with azathioprine/6-MP, the white blood cell count was significantly lower in patients with theMRP4 variant alone (n = 26) than in patients with a wild allelotype (n = 74) (P = 0.014) or in patients with the ITPase variant alone (n = 22) (P = 0.0095). The 6-TGN levels were significantly higher in patients with the MRP4 variant alone than in patients with the wild allelotype(P = 0.049). Of the 15 patients who experienced leucopenia (<3 x 10⁹/l), 7 patients carried the MRP4 variant.The odds ratio of carrying the MRP4 variant alone and having leukopenia was 3.30 (95% confidence interval 1.03–10.57, P = 0.036).

Conclusions: These results suggest that MRP4 G2269A might be a new factor accounting for thiopurine sensitivity in Japanese patients with IBD.

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Azathioprine / metabolism
  • Azathioprine / therapeutic use
  • Colitis, Ulcerative / drug therapy*
  • Colitis, Ulcerative / genetics
  • Crohn Disease / drug therapy*
  • Crohn Disease / genetics
  • Exons
  • Female
  • Humans
  • Immunosuppressive Agents / metabolism
  • Immunosuppressive Agents / therapeutic use*
  • Japan
  • Male
  • Mercaptopurine / metabolism
  • Mercaptopurine / therapeutic use
  • Middle Aged
  • Multidrug Resistance-Associated Proteins / genetics*
  • Polymerase Chain Reaction / methods
  • Polymorphism, Single Nucleotide
  • Sequence Analysis, DNA
  • Young Adult


  • ABCC4 protein, human
  • Immunosuppressive Agents
  • Multidrug Resistance-Associated Proteins
  • Mercaptopurine
  • Azathioprine