Pharmacogenetics of azathioprine in inflammatory bowel disease: A role for glutathione-S-transferase?

Stocco, Gabriele; Pelin, Marco; Franca, Raffaella; Iudicibus, Sara De; Cuzzoni, Eva; Favretto, Diego; Martelossi, Stefano; Ventura, Alessandro; Decorti, Giuliana

doi:10.3748/wjg.v20.i13.3534

Cited by 44 publications

(41 citation statements)

References 49 publications

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“…It has been postulated that depletion of cellular stores of GSH causes early azathioprinespecific cytotoxicity [69]. Conversion of azathioprine to 6-MP depletes GSH which in turn leads to accumulation of reactive oxygen species and induction of cell apoptosis [69]. In vitro studies support this notion.…”

Section: Glutathione-s-transferase Deficiency Associated With a Decrementioning

confidence: 92%

“…The high affinity for azathioprine and the predominant expression of these GSTs in hepatocytes, suggest that the genetic poly morphisms in these GSTs may well translate into marked patient-to-patient differences in the amount and rate at which azathioprine is converted to 6-MP [69]. GSH is largely responsible for maintaining the redox balance within cells and protecting against oxidative stress [70,71].…”

Section: Glutathione-s-transferase Deficiency Associated With a Decrementioning

confidence: 98%

“…GSH is largely responsible for maintaining the redox balance within cells and protecting against oxidative stress [70,71]. It has been postulated that depletion of cellular stores of GSH causes early azathioprinespecific cytotoxicity [69]. Conversion of azathioprine to 6-MP depletes GSH which in turn leads to accumulation of reactive oxygen species and induction of cell apoptosis [69].…”

Section: Glutathione-s-transferase Deficiency Associated With a Decrementioning

confidence: 99%

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Update on Thiopurine Pharmacogenetics in Inflammatory Bowel Disease

Roberts

Barclay

2015

Pharmacogenomics

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Azathioprine and 6-mercaptopurine remain pivotal therapies for the maintenance of disease remission in patients with Crohn's disease and ulcerative colitis. While thiopurine S-methyltransferase deficiency was the first pharmacogenetic phenomenon to be recognized to influence thiopurine toxicity and reliably predict leukopenia, it does not predict other adverse effects, nor does it explain most cases of thiopurine resistance. In recent years, a number of other genetic polymorphisms have received increasing attention in the literature. In particular, SNPs in NUDT15 and in the class II HLA locus have been shown to predict thiopurine-related leukopenia and pancreatitis. The aim of this review is to provide a concise update of genetic variability which may influence patient response to azathioprine and 6-mercaptopurine.

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Section: Glutathione-s-transferase Deficiency Associated With a Decrementioning

confidence: 92%

Section: Glutathione-s-transferase Deficiency Associated With a Decrementioning

confidence: 98%

Section: Glutathione-s-transferase Deficiency Associated With a Decrementioning

confidence: 99%

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Update on Thiopurine Pharmacogenetics in Inflammatory Bowel Disease

Roberts

Barclay

2015

Pharmacogenomics

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“…Previous studies also have suggested that several GSTs genotypes are associated with poor clinical response to azathioprine in IBD patients. This result indicates the important roles of GSTs in the development of IBD [43, 44]. However, it is still unclear whether the GSTT1 null genotype is associated with clinical response or outcomes in IBD patients and future studies are needed to explore this possibility.…”

Section: Discussionmentioning

confidence: 99%

Glutathione S-Transferase T1 Null Genotype is Associated with Susceptibility to Inflammatory Bowel Disease

Qian¹,

Song

et al. 2017

Cell Physiol Biochem

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Background: The published literature contains conflicting results regarding the impact of the glutathione S-transferase T1 (GSTT1) null genotype on the susceptibility to inflammatory bowel disease. Therefore, we conducted a meta-analysis of observational studies to assess the association. Methods: We searched four online databases for eligible studies. The odds ratio (OR) with 95% CI was used to assess the gene-disease association. We also performed subgroup analyses by type of inflammatory bowel disease and ethnicity. Results: There were 16 individual studies from 11 publications included in the analysis. There were 3366 cases with inflammatory bowel disease and 6013 controls. The meta-analysis of all 16 studies showed the GSTT1 null genotype was associated with increased susceptibility to inflammatory bowel disease (OR = 1.98, 95%CI 1.39-2.84, P < 0.001). The subgroup analysis by ethnicity further identified an association between the GSTT1 null genotype and inflammatory bowel disease in Caucasians, Asians, and Africans. The GSTT1 null genotype was associated with both ulcerative colitis (OR = 1.96, P = 0.004) and Crohn’s disease (OR = 2.01, P = 0.022). The GSTT1 null genotype was still significantly associated with ulcerative colitis (OR = 1.63, P < 0.0001) and Crohn’s disease (OR = 1.40, P = 0.023) after adjusting for study heterogeneity. Conclusion: The GSTT1 null genotype is significantly associated with an increased susceptibility to inflammatory bowel disease and is a risk factor for both ulcerative colitis and Crohn’s disease.

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“…However, there have also been reports that GSTP1 variants may be associated with more favorable outcomes with certain chemotherapeutic agents, such as cyclophosphamide, adriamycin, and oxaliplatin [87] , and there was a decreased risk of developing the cumulative neuropathy that is a major dose-limiting toxicity of treatment with oxaliplatin [88] . Furthermore, the conversion of azathioprine from its pro-drug form to the active metabolite mercaptopurine, an immunosuppressive compound, may be impaired in carriers of null alleles of GSTM1 reducing the production of azathioprine active metabolites [89] . Therefore, the pharmacogenetics of GSTP1 and GSTM1 may be useful in the prediction of response to such drugs, even though these findings should be confirmed by a larger number of patients in ongoing clinical studies.…”

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confidence: 99%

Pharmacogenetics of drug-metabolizing enzymes in Italian populations

Serpe

Canaparo

Scordo

et al. 2014

Drug Metabolism and Personalized Therapy

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: Drug-metabolizing enzymes play a major role in the biotransformation and subsequent elimination of most drugs and xenobiotics from the body. Both phase I and phase II enzymes are highly polymorphic. Inter-individual differences in genes coding for drug-metabolizing enzymes are important for understanding variability in drug response and for individualization of drug prescription. The prevalence of genetic polymorphisms in drug metabolism varies widely with ethnicity, and marked differences in the distribution of allelic variants of genes encoding drug-metabolizing enzymes have been documented in populations of different racial origin. This review aimed to summarize the available studies on genetic polymorphisms associated with drug metabolism conducted in Italian populations and to compare the frequency of the various metabolizer phenotypes and most common variant alleles (and resulting genotypes) with corresponding values from other populations. Notably, published data are not extensive, and most studies were performed on relatively low numbers of individuals. In general, the frequency of polymorphisms in the cytochrome P450 ( CYP ) genes as well as in the investigated phase II enzymes in the Italian population was similar to values reported for other Caucasian populations. However, the prevalence of CYP2D6 gene duplication among Italians was found to be very high, confirming the higher frequency of CYP2D6 ultrarapid metabolizers in the Mediterranean area compared to Northern Europe. It is worth noting that a geographic gradient in the flavin-containing monooxygenase 3 polymorphism distribution was also seen, the Italian population showing higher similarity to other Mediterranean populations than to North Europeans.

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Pharmacogenetics of azathioprine in inflammatory bowel disease: A role for glutathione-S-transferase?

Cited by 44 publications

References 49 publications

Update on Thiopurine Pharmacogenetics in Inflammatory Bowel Disease

Update on Thiopurine Pharmacogenetics in Inflammatory Bowel Disease

Glutathione S-Transferase T1 Null Genotype is Associated with Susceptibility to Inflammatory Bowel Disease

Pharmacogenetics of drug-metabolizing enzymes in Italian populations

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