title: The glutathione transferase Mu null genotype leads to lower 6-MMPR levels in patients treated with azathioprine but not with mercaptopurine.
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 × 108RBCs; P<0.01). In patients on MP (control group) 6-MMPR levels were comparable (6195 (1551-10712) versus 6544 (1717-11600) pmol/8 × 108RBCs; 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.
authors.affiliation: Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Department of Gastroenterology, Nijmegen, The Netherlands.
authors.forename: M M T J
authors.initials: MMTJ
authors.lastname: Broekman
authors.affiliation: Department of Clinical Pharmacy, Pharmacology and Toxicology, Zuyderland Medical Center, Sittard-Geleen, The Netherlands.
authors.forename: D R
authors.initials: DR
authors.lastname: Wong
authors.affiliation: Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Department of Gastroenterology, Nijmegen, The Netherlands.
authors.forename: G J A
authors.initials: GJA
authors.lastname: Wanten
authors.affiliation: Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Department of Gastroenterology, Nijmegen, The Netherlands.
authors.forename: H M
authors.initials: HM
authors.lastname: Roelofs
authors.affiliation: Radboud University Medical Center, Radboud Institute for Health Sciences, Department of Human Genetics, Nijmegen, The Netherlands.
authors.forename: C J
authors.initials: CJ
authors.lastname: van Marrewijk
authors.affiliation: Department of Pharmacoepidemiology and Pharmacotherapy, Utrecht University, Utrecht, The Netherlands.
authors.forename: O H
authors.initials: OH
authors.lastname: Klungel
authors.affiliation: Radboud University Medical Center, Radboud Institute for Health Sciences, Nijmegen, The Netherlands.
authors.forename: A L M
authors.initials: ALM
authors.lastname: Verbeek
authors.affiliation: Department of Clinical Pharmacy, Pharmacology and Toxicology, Zuyderland Medical Center, Sittard-Geleen, The Netherlands.
authors.forename: P M
authors.initials: PM
authors.lastname: Hooymans
authors.affiliation: Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: H-J
authors.initials: HJ
authors.lastname: Guchelaar
authors.affiliation: Radboud University Medical Center, Radboud Institute for Health Sciences, Department of Human Genetics, Nijmegen, The Netherlands.
authors.forename: H
authors.initials: H
authors.lastname: Scheffer
authors.affiliation: Department of Clinical Pharmacy, Máxima Medical Center, Veldhoven, The Netherlands.
authors.forename: L J J
authors.initials: LJJ
authors.lastname: Derijks
authors.affiliation: Radboud University Medical Center, Radboud Institute for Health Sciences, Department of Human Genetics, Nijmegen, The Netherlands.
authors.forename: M J H
authors.initials: MJH
authors.lastname: Coenen
authors.affiliation: Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Department of Gastroenterology, Nijmegen, The Netherlands.
authors.forename: D J
authors.initials: DJ
authors.lastname: de Jong
mesh_terms: D000328:Adult; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use*; D001379:Azathioprine / Q000378:metabolism / Q000627:therapeutic use*; D016022:Case-Control Studies; D005260:Female; D005838:Genotype; D005982:Glutathione Transferase / Q000235:genetics*; D006150:Guanine Nucleotides / Q000235:genetics; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D015212:Inflammatory Bowel Diseases / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D007527:Isoenzymes / Q000235:genetics; D008297:Male; D015122:Mercaptopurine / Q000378:metabolism; D008875:Middle Aged; D013868:Thioinosine / Q000031:analogs & derivatives* / Q000378:metabolism; D013873:Thionucleotides / Q000235:genetics / Q000378:metabolism*; D055815:Young Adult
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D001379:Azathioprine; D005982:Glutathione Transferase; D006150:Guanine Nucleotides; D007166:Immunosuppressive Agents; D007527:Isoenzymes; D015122:Mercaptopurine; D013868:Thioinosine; D013873:Thionucleotides; C003964:6-thioguanylic acid; C002344:6-methylthiopurine ribonucleoside-5'-phosphate; C119995:glutathione S-transferase alpha