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

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; D J de Jong

doi:10.1038/tpj.2016.87

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

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
, D J de Jong

Research output: Contribution to journal › Article › Academic › peer-review

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.

Original language	English
Pages (from-to)	160-166
Number of pages	7
Journal	Pharmacogenomics Journal
Volume	18
Issue number	1
DOIs	https://doi.org/10.1038/tpj.2016.87
Publication status	Published - Jan 2018
Externally published	Yes

Keywords

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

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10.1038/tpj.2016.87

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Broekman, M. M. T. J., Wong, D. R., Wanten, G. J. A., Roelofs, H. M., van Marrewijk, C. J., Klungel, O. H., Verbeek, A. L. M., Hooymans, P. M., Guchelaar, H.-J., Scheffer, H., Derijks, L. J. J., Coenen, M. J. H., & de Jong, D. J. (2018). The glutathione transferase Mu null genotype leads to lower 6-MMPR levels in patients treated with azathioprine but not with mercaptopurine. Pharmacogenomics Journal, 18(1), 160-166. https://doi.org/10.1038/tpj.2016.87

@article{7f83b6bdf64b4af28358698be2a7c1e6,

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 × 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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author = "Broekman, \{M M T J\} and Wong, \{D R\} and Wanten, \{G J A\} and Roelofs, \{H M\} and \{van Marrewijk\}, \{C J\} and Klungel, \{O H\} and Verbeek, \{A L M\} and Hooymans, \{P M\} and H-J Guchelaar and H Scheffer and Derijks, \{L J J\} and Coenen, \{M J H\} and \{de Jong\}, \{D J\}",

year = "2018",

month = jan,

doi = "10.1038/tpj.2016.87",

language = "English",

volume = "18",

pages = "160--166",

journal = "Pharmacogenomics Journal",

issn = "1470-269X",

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Broekman, MMTJ, Wong, DR, Wanten, GJA, Roelofs, HM, van Marrewijk, CJ, Klungel, OH, Verbeek, ALM, Hooymans, PM, Guchelaar, H-J, Scheffer, H, Derijks, LJJ, Coenen, MJH & de Jong, DJ 2018, 'The glutathione transferase Mu null genotype leads to lower 6-MMPR levels in patients treated with azathioprine but not with mercaptopurine', Pharmacogenomics Journal, vol. 18, no. 1, pp. 160-166. https://doi.org/10.1038/tpj.2016.87

TY - JOUR

T1 - The glutathione transferase Mu null genotype leads to lower 6-MMPR levels in patients treated with azathioprine but not with mercaptopurine

AU - Broekman, M M T J

AU - Wong, D R

AU - Wanten, G J A

AU - Roelofs, H M

AU - van Marrewijk, C J

AU - Klungel, O H

AU - Verbeek, A L M

AU - Hooymans, P M

AU - Guchelaar, H-J

AU - Scheffer, H

AU - Derijks, L J J

AU - Coenen, M J H

AU - de Jong, D J

PY - 2018/1

Y1 - 2018/1

N2 - 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.

AB - 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.

KW - Adult

KW - Anti-Inflammatory Agents, Non-Steroidal/therapeutic use

KW - Azathioprine/metabolism

KW - Case-Control Studies

KW - Female

KW - Genotype

KW - Glutathione Transferase/genetics

KW - Guanine Nucleotides/genetics

KW - Humans

KW - Immunosuppressive Agents/therapeutic use

KW - Inflammatory Bowel Diseases/drug therapy

KW - Isoenzymes/genetics

KW - Male

KW - Mercaptopurine/metabolism

KW - Middle Aged

KW - Thioinosine/analogs & derivatives

KW - Thionucleotides/genetics

KW - Young Adult

U2 - 10.1038/tpj.2016.87

DO - 10.1038/tpj.2016.87

M3 - Article

C2 - 28045129

SN - 1470-269X

VL - 18

SP - 160

EP - 166

JO - Pharmacogenomics Journal

JF - Pharmacogenomics Journal

IS - 1

ER -

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

Abstract

Keywords

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