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

The Pharmacogenomics Journal volume 18, pages 160–166 (2018)Cite this article

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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.

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Acknowledgements

We are deeply indebted to the participants of the TOPIC trial. We thank Rene H.M. te Morsche, J. Salomon and Wilbert H.M. Peters from the Department of Gastroenterology, Radboud University Medical Center, Nijmegen, The Netherlands, for the measurement of TPMT activity, assistance with PCRs and interpretation of data. Furthermore, we thank Mariëlle Maas, Miet Fiddelaers, Milevis Reitsma, Leonie Peters and Jean Cilissen from the Department of Clinical Pharmacy and Toxicology, Zuyderland Medical Center, Sittard-Geleen, The Netherlands for technical assistance with metabolite measurements and Debbie Heinen, Marjolein M.J. van Donkelaar, Freshteh Golestani, Marlies E. de Vos, J.G. Angelien M. Heister, Doménique M.W. Nijsten, Mascha M.V.A.P. Schijvenaars, and Martine E.C. Cranen from the Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands for their support in data-management. We thank Dr Sita H. Vermeulen, Department of Health Evidence, Radboud University Medical Center, Nijmegen, The Netherlands, and Prof. Dr Barbara Franke, Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands, for their contribution to the design of the TOPIC trial. At last, we thank Prof. Dr Joost P.H. Drenth from the Department of Gastroenterology, Radboud University Medical Center, Nijmegen, The Netherlands, for intellectual contributions to the content of the manuscript.

AAM Masclee8, M Pierik8, W Mares8, W Hameeteman8, PJ Wahab9, H Seinen9, MCM Rijk10, IM Harkema10, M de Bièvre11, L Oostenbrug11, CM Bakker11, M Aquarius11, C van Deursen11, AB van Nunen11, JG Goedhard11, M Hamacher11, IAM Gisbertz12, BJ Brenninkmeijer12, ACITL Tan13, MN Aparicio-Pagés13, EM Witteman13, SAC van Tuyl14, R Breumelhof14, A Stronkhorst15, LPL Gilissen15, EJ Schoon15, JWM Tjhie-Wensing16, A Temmerman16, JJ Nicolaï17, JD van Bergeijk18, DJ Bac18, BJM Witteman18, N Mahmmod18, JJ Uil18, H Akol18, RJTh Ouwendijk19, IP van Munster20, M Pennings20, AMP De Schryver20, ThJM van Ditzhuijsen20, RCH Scheffer20, TEH Römkens20, DL Schipper20, PJ Bus21, JWA Straathof22, ML Verhulst22, PJ Boekema22, JTh Kamphuis22, HJ van Wijk22, JMJL Salemans22, JR Vermeijden23, SDJ van der Werf24, RJ Verburg24, P Spoelstra25, JML de Vree25, K van der Linde25, HJA Jebbink25, M. Jansen25, H. Holwerda25, N van Bentem26, JJ Kolkman26, MGVM Russel26, GH van Olffen26, MJ Kerbert-Dreteler26, M Bargeman26, JM Götz26, R Schröder26, JM Jansen27, LP Bos28, LGJB Engels28, MJL Romberg-Camps28, ETP Keulen28, AAJ van Esch29, JPH Drenth29, MCA van Kouwen29, GJA Wanten29, TJ Bisseling29, TEH Römkens29, MWJ van Vugt29, PC van de Meeberg30, SJ van den Hazel30, WNHM Stuifbergen31, MJAL Grubben31, U de Wit31, GAH Dodemont31, RF Eichhorn31, JMH van den Brande32, AHJ Naber32, EJ van Soest32, PJ Kingma32, NC Talstra33, KF Bruin33, FHJ Wolfhagen33, DW Hommes34, PPJ van der Veek34, JCA Hardwick34, RJ Stuyt34, HH Fidder34, B Oldenburg35, TG Tan36

8Department of Gastroenterology, Academisch Ziekenhuis Maastricht, Maastricht, The Netherlands, 9Department of Gastroenterology, Rijnstate Ziekenhuis Arnhem, Arnhem, The Netherlands, 10Department of Gastroenterology, Amphia Ziekenhuis, Breda, The Netherlands, 11Department of Gastroenterology, Atrium Medisch Centrum, Heerlen, The Netherlands, 12Department of Gastroenterology, Bernhoven Hospital, Oss, The Netherlands, 13Department of Gastroenterology, Canisius Wilhelmina Ziekenhuis, Nijmegen, The Netherlands, 14Department of Gastroenterology, Diakonessenhuis, Utrecht, The Netherlands, 15Department of Gastroenterology, Catharina Ziekenhuis, Eindhoven, The Netherlands, 16Department of Gastroenterology, Elkerliek Ziekenhuis, Helmond, The Netherlands, 17HagaZiekenhuis, ‘s-Gravenhage, The Netherlands, 18Department of Gastroenterology, Gelderse Vallei Hospital, Ede, The Netherlands, 19Department of Gastroenterology, Ikazia Hospital, Rotterdam, The Netherlands, 20Department of Gastroenterology, Jeroen Bosch Hospital, ‘s-Hertogenbosch, The Netherlands, 21Department of Gastroenterology, Laurentius Hospital, Roermond, The Netherlands, 22Department of Gastroenterology, Máxima Medisch Centrum, Eindhoven-Veldhoven, The Netherlands, 23Department of Gastroenterology, Meander MC, Amersfoort, The Netherlands, 24Department of Gastroenterology, MC Haaglanden, Den Haag, The Netherlands, 25Department of Gastroenterology, Medisch Centrum Leeuwarden, Leeuwarden, The Netherlands, 26Department of Gastroenterology, Medisch Spectrum Twente, Enschede, The Netherlands, 27Department of Gastroenterology, Onze Lieve Vrouwe Gasthuis, Amsterdam, The Netherlands, 28Department of Gastroenterology, Orbis Medisch Centrum, Sittard-Geleen, The Netherlands, 29Department of Gastroenterology, Radboud university medical center, Nijmegen, The Netherlands, 30Department of Gastroenterology, Slingeland Hospital, Doetinchem, The Netherlands, 31Department of Gastroenterology, St Elisabeth Ziekenhuis, Tilburg, The Netherlands, 32Department of Gastroenterology, Tergooiziekenhuizen, Blaricum-Hilversum, The Netherlands, 33Department of Gastroenterology, TweeSteden Ziekenhuis, Tilburg, The Netherlands, 34Department of Gastroenterology, University Medical Centre Leiden, Leiden, The Netherlands, 35Department of Gastroenterology, University Medical Centre Utrecht, Utrecht, The Netherlands, 36Department of Gastroenterology, Ziekenhuisgroep Twente, Hengelo, The Netherlands.

Author contributions

Study design: MB, GW, DW, MC, DJ. Performed experiments: MB, HR. Metabolite measurements: DW, PH. Data collection: MB, CM, MC, DW. Data analysis: MB, HR, MC. Writing of the manuscript: MB, DW, GW, DJ, MC. Interpretation of data and critical revision of the manuscript for important intellectual content: HG, AV, HS, LD, OK, HR. Study supervision: DJ, MC.

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Author notes

  1. M M T J Broekman, D R Wong, G J A Wanten, H M Roelofs, C J van Marrewijk, O H Klungel, A L M Verbeek, P M Hooymans, H-J Guchelaar, H Scheffer, L J J Derijks, M J H Coenen and D J de Jong: TOPIC recruitment team: The TOPIC recruitment team was responsible for patient recruitment and collection of clinical data. Compensation was given to the members of the recruitment team for additional biochemical measurements and examinations that had to be performed for the TOPIC study. TOPIC recruitment team members are listed in Acknowledgements section.

Authors and Affiliations

  1. Department of Gastroenterology, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands

    M M T J Broekman, G J A Wanten, H M Roelofs & D J de Jong

  2. Department of Clinical Pharmacy, Pharmacology and Toxicology, Zuyderland Medical Center, Sittard-Geleen, The Netherlands

    D R Wong & P M Hooymans

  3. Department of Human Genetics, Radboud University Medical Center, Radboud Institute for Health Sciences, Nijmegen, The Netherlands

    C J van Marrewijk, H Scheffer & M J H Coenen

  4. Department of Pharmacoepidemiology and Pharmacotherapy, Utrecht University, Utrecht, The Netherlands

    O H Klungel

  5. Radboud University Medical Center, Radboud Institute for Health Sciences, Nijmegen, The Netherlands

    A L M Verbeek

  6. Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden, The Netherlands

    H-J Guchelaar

  7. Department of Clinical Pharmacy, Máxima Medical Center, Veldhoven, The Netherlands

    L J J Derijks

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Broekman, M., Wong, D., Wanten, G. et al. The glutathione transferase Mu null genotype leads to lower 6-MMPR levels in patients treated with azathioprine but not with mercaptopurine. Pharmacogenomics J 18, 160–166 (2018). https://doi.org/10.1038/tpj.2016.87

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