The glutathione transferase Mu null genotype leads to lower 6-MMPR levels in patients treated with azathioprine but not with mercaptopurine

Pharmacogenomics J. 2018 Jan;18(1):160-166. doi: 10.1038/tpj.2016.87. Epub 2017 Jan 3.

Abstract

The conversion of azathioprine (AZA) to mercaptopurine (MP) is mediated by glutathione transferase Mu1 (GSTM1), alpha1 (GSTA1) and alpha2 (GSTA2). We designed a case-control study with data from the TOPIC trial to explore the effects of genetic variation on steady state 6-methylmercaptopurine ribonucleotide (6-MMPR) and 6-thioguanine nucleotide (6-TGN) metabolite levels. We included 199 patients with inflammatory bowel disease (126 on AZA and 73 on MP). GSTM1-null genotype carriers on AZA had two-fold lower 6-MMPR levels than AZA users carrying one or two copies of GSTM1 (2239 (1006-4587) versus 4371 (1897-7369) pmol/8 × 108 RBCs; P<0.01). In patients on MP (control group) 6-MMPR levels were comparable (6195 (1551-10712) versus 6544 (1717-11600) pmol/8 × 108 RBCs; P=0.84). The 6-TGN levels were not affected by the GSTM1 genotype. The presence of genetic variants in GSTA1 and GSTA2 was not related to the 6-MMPR and 6-TGN levels.

MeSH terms

  • Adult
  • Anti-Inflammatory Agents, Non-Steroidal / therapeutic use*
  • Azathioprine / metabolism
  • Azathioprine / therapeutic use*
  • Case-Control Studies
  • Female
  • Genotype
  • Glutathione Transferase / genetics*
  • Guanine Nucleotides / genetics
  • Humans
  • Immunosuppressive Agents / therapeutic use*
  • Inflammatory Bowel Diseases / drug therapy
  • Inflammatory Bowel Diseases / genetics
  • Inflammatory Bowel Diseases / metabolism
  • Isoenzymes / genetics
  • Male
  • Mercaptopurine / metabolism
  • Middle Aged
  • Thioinosine / analogs & derivatives*
  • Thioinosine / metabolism
  • Thionucleotides / genetics
  • Thionucleotides / metabolism*
  • Young Adult

Substances

  • Anti-Inflammatory Agents, Non-Steroidal
  • Guanine Nucleotides
  • Immunosuppressive Agents
  • Isoenzymes
  • Thionucleotides
  • 6-thioguanylic acid
  • Thioinosine
  • 6-methylthiopurine ribonucleoside-5'-phosphate
  • Mercaptopurine
  • Glutathione Transferase
  • glutathione S-transferase M1
  • glutathione S-transferase alpha
  • Azathioprine