Differences among allelic variants of human glutathione transferase A2-2 in the activation of azathioprine

Zhang, Wei; Modén, Olof; Mannervik, Bengt

doi:10.1016/j.cbi.2010.04.028

Cited by 26 publications

(13 citation statements)

References 34 publications

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“…36 Nevertheless, in the liver, the GSTA2 S112T locus has been found to impact the GSTA2 protein level and themostability. 24,27 These data suggest that the GSTA2 S112T locus affects the individual capability to metabolize busulfan, independently of the alteration of GSTA2 enzyme activity.…”

Section: Discussionmentioning

confidence: 89%

“…27 Busulfan is almost exclusively metabolized in the liver, where GSTA2 is expressed. 15,28 Anova analysis using age, gender, BMI and source of HSC as covariates, revealed higher systemic exposure to busulfan (Day -3 AUC) in GSTA2 S112T ser/ser patients compared to thr+ (1214.36+570.06 vs. 838.10+282.40 mMol*min, F=9.185; P=0.001) (Figure 2A) Because glutathione depletion causes liver damage, 18 we then evaluated the association between GSTA2 S112T F. Bonifazi et al 174 haematologica | 2014; 99(1) SNP and liver function tests: total bilirubin, alanine transaminase, aspartate transaminase, cholinesterase, alkaline phosphatase and gamma-glutamyl transferase were examined weekly from the day of conditioning, up to Day 35 post transplant.…”

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confidence: 99%

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Glutathione transferase-A2 S112T polymorphism predicts survival, transplant-related mortality, busulfan and bilirubin blood levels after allogeneic stem cell transplantation

et al. 2013

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Methods PatientsThe busulfan cohort was made up of 185 consecutive patients (Table 1) who were transplanted at the Institute of Hematology "L. and A. Seràgnoli", University of Bologna, Italy, between 2005 and 2009, using busulfan as conditioning. Myeloablative conditioning (0.8 mg/kg intravenous busulfan, 2-h infusions, four times a day, four consecutive days plus cyclophosphamide, 120 mg/kg) was administered to 167 patients. Lower (6 patients) or standard busulfan doses plus fludarabine 160 mg/m 2 (12 patients) were also used. Ideal body weight (IBW) was calculated as 0.91 x (height in cm -152) +50 (for men) or +45 (for women). IBW was used when lower than the actual weight and when body mass index (BMI) was lower/equal to 27. When BMI was greater than 27, IBW was adjusted as IBW+ 0.25 x (actual weight -IBW).A total of 146 consecutive patients (comparator cohort, Table 1) transplanted at the same Institution were also studied. In this cohort, the myeloablative conditioning was cyclophosphamide (120 mg/kg) plus unfractionated total body irradiation (8 Gy).Graft-versus-host disease prophylaxis was cyclosporin-A and short-term methotrexate plus rabbit anti-thymocyte globulin (3-5 mg/kg/die, Fresenius, Bad-Homburg, Germany), from Day -6 to Day -2. Patients with acute leukemia in first complete remission or with chronic myeloid leukemia in first chronic phase were classified as being in early phase at transplant; the remaining patients were classified as being in advanced phase. Written informed consent for the study was obtained from all patients. The study was approved by the Ethics Committee

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Section: Discussionmentioning

confidence: 89%

mentioning

confidence: 99%

Glutathione transferase-A2 S112T polymorphism predicts survival, transplant-related mortality, busulfan and bilirubin blood levels after allogeneic stem cell transplantation

et al. 2013

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“…Their catalytic activities depend on genetic polymorphisms. Concerning GST A2‐2, five allelic variants were associated with high activity towards AZA, but specifically one allelic variant, GST‐A2‐2*E, displays a three‐ to fourfold elevated activity 201 . Based on these results, Elkund et al.…”

Section: Newly Identified Pharmacogenetic Factors Contributing To Varmentioning

confidence: 92%

Review article: the benefits of pharmacogenetics for improving thiopurine therapy in inflammatory bowel disease

Chouchana

Narjoz

Beaune

et al. 2011

Aliment Pharmacol Ther

149

142

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Aliment Pharmacol Ther 2012; 35: 15–36 Summary Background Thiopurines represent an effective and widely prescribed therapy in inflammatory bowel disease (IBD). Concerns about toxicity, mainly resulting from a wide inter‐individual variability in thiopurine metabolism, restrict their use. Optimal thiopurine dosing is challenging for preventing adverse drug reactions and improving clinical response. Aim To review efficacy and toxicity of thiopurines in IBD. To provide pharmacogenetic‐based therapeutic recommendations. Methods We conducted a query on PubMed database using ‘inflammatory bowel disease’, ‘thiopurine’, ‘azathioprine’, ‘6‐mercaptopurine’, ‘TPMT’, ‘pharmacogenetics’, ‘TDM’, and selected relevant articles, especially clinical studies. Results Thiopurine metabolism – key enzyme: thiopurine S‐methyltransferase (TPMT) – modulates clinical response, as it results in production of the pharmacologically active and toxic metabolites, the thioguanine nucleotides (6‐TGN). Adjusting dosage according to TPMT status and/or metabolite blood levels is recommended for optimising thiopurine therapy (e.g. improving response rate up to 30% or decreasing haematological adverse events of 25%). Other enzymes or transporters of interest, as inosine triphosphatase (ITPase), glutathione S‐transferase (GST), xanthine oxidase (XO), aldehyde oxidase (AOX), methylene tetrahydrofolate reductase (MTHFR) and ATP‐binding cassette sub‐family C member 4 (ABCC4) are reviewed and discussed for clinical relevance. Conclusions Based on the literature data, we provide a therapeutic algorithm for thiopurines therapy with starting dose recommendations depending on TPMT status and thereafter dose adjustments according to five metabolite profiles identified with therapeutic drug monitoring (TDM). This algorithm allows a dosage individualisation to optimise the management of patients under thiopurine. Furthermore, identification of new pharmacogenetic biomarkers is promising for ensuring maximal therapeutic response to thiopurines with a minimisation of the risk for adverse events.

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“…Azathioprine is converted nonenzymatically to MP mainly through a reaction with glutathione, and some studies have suggested that glutathione S‐transferase (GST) might also be involved . The catalytic activities of GST vary according to genetic polymorphism . Individuals expressing high GST activity are potentially predisposed for adverse effects to AZA treatment, both by promoting excessively high concentrations of free MP and its toxic metabolites, and by depletion of cellular glutathione .…”

Section: Resultsmentioning

confidence: 99%

Review article: recent advances in pharmacogenetics and pharmacokinetics for safe and effective thiopurine therapy in inflammatory bowel disease

Moon

Loftus

2016

Aliment Pharmacol Ther

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Differences among allelic variants of human glutathione transferase A2-2 in the activation of azathioprine

Cited by 26 publications

References 34 publications

Glutathione transferase-A2 S112T polymorphism predicts survival, transplant-related mortality, busulfan and bilirubin blood levels after allogeneic stem cell transplantation

Glutathione transferase-A2 S112T polymorphism predicts survival, transplant-related mortality, busulfan and bilirubin blood levels after allogeneic stem cell transplantation

Review article: the benefits of pharmacogenetics for improving thiopurine therapy in inflammatory bowel disease

Review article: recent advances in pharmacogenetics and pharmacokinetics for safe and effective thiopurine therapy in inflammatory bowel disease

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