Hypoxanthine guanine phosphoribosyltransferase activity is related to 6-thioguanine nucleotide concentrations and thiopurine-induced leukopenia in the treatment of inflammatory bowel disease

Ding, Liang; Zhang, Fangbin; Liu, Hui; Gao, Xiang; Bi, Huichang; Wang, Xueding; Chen, Baili; Zhong, Yu; Lizi, Zhao; Zhong, Guoping; Hu, Pinjin; Chen, Minhu; Huang, Ming

doi:10.1002/ibd.21676

Cited by 34 publications

(36 citation statements)

References 65 publications

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“…No case with TPMT mutation was found in our study. Therefore, other genetic and epigenetic factors must play a role in the incidence of the ADRs, including ITPA (21), hypoxanthine guanine phosphoribosyltransferase (HPRT) (22), and GST (6).…”

Section: Discussionmentioning

confidence: 99%

The impact of glutathione S–transferase genotype and phenotype on the adverse drug reactions to azathioprine in patients with inflammatory bowel diseases

Liu

Ding

Zhang

et al. 2015

Journal of Pharmacological Sciences

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Azathioprine (AZA) is a thiopurine prodrug which is widely used in patients with inflammatory bowel disease (IBD). However, the use is limited in one-third of patients because of adverse drug reactions (ADRs) or a lack of clinical response. It has been considered that the polymorphic enzyme thiopurine S-methyltransferase (TPMT) plays an important role in the in vivo process of AZA and the occurrence of its myelotoxicity. Glutathione S-transferase (GST) mutation is another pharmacogenetic polymorphism which is probably involved in AZA metabolism and tolerance. The aim of this study was to investigate the association among GST polymorphism, enzyme activity and AZA-related ADRs in Chinese Han patients with IBD. We found that the patients who became neutropenic had a significantly higher GSTs activity when compared with of the patients who did not develop ADRs (analysis of variance, P < 0.001). There was also a significant underrepresentation of GSTP1*-105V allele among patients developing ADRs (odds ratio [OR] = 0.125, 95% confidence interval [CI] = 0.022-0.709, P = 0.0012). The patients with higher GST activity constituted a pharmacogenetic high risk group for leucopenia during AZA treatment. GST-P1 Ile105/Ile105 genotype appeared to be a promising marker indicating predisposition to AZA-related ADRs.

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Section: Discussionmentioning

confidence: 99%

The impact of glutathione S–transferase genotype and phenotype on the adverse drug reactions to azathioprine in patients with inflammatory bowel diseases

Liu

Ding

Zhang

et al. 2015

Journal of Pharmacological Sciences

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“…[16] Safety monitoring by regular blood counts is therefore essential, specifically in patients with this combination therapy, as they have an increased risk of developing myelotoxicity.…”

Section: Discussionmentioning

confidence: 99%

Allopurinol Enhances the Activity of Hypoxanthine-Guanine Phosphoribosyltransferase in Inflammatory Bowel Disease Patients During Low-Dose Thiopurine Therapy: Preliminary Data of an Ongoing Series

Seinen¹,

Boer²,

Smid³

et al. 2011

Nucleosides, Nucleotides and Nucleic Acids

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Thiopurines are crucial in the treatment of inflammatory bowel disease. The phenotype of pivotal metabolic enzymes determines whether thioguanine nucleotides (6-TGN) are generated in clinically sufficiently high levels. The first step in activation of thiopurine prodrugs to 6-TGN is catalysis by hypoxanthine-guanine phosphoribosyltransferase (HGPRT). Often, patients exhibit a clinically unfavorable metabolism, leading to discontinuation of conventional thiopurine therapy. The combination of allopurinol and low-dose thiopurine therapy may optimize this variant metabolism, presumably by affecting enzyme activities. We performed a prospective pharmacodynamic study to determine the effect of combination therapy on the activity of HGPRT. The activity of HGPRT and 6-TGN concentrations was measured in red blood cells during thiopurine monotherapy and after 4 weeks of combination therapy. The activity of HGPRT was also measured after 12 weeks of combination therapy. From the results, we conclude that combination therapy increases the activity of HGPRT and subsequently 6-TGN concentrations.

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“…25 Ding and colleagues recently reported a correlation between the activity of HGPRT and 6-TGN concentrations, which was not observed in this study possibly due the small sample size. 31 Nonetheless, the enhanced HGPRT activity may at least in part explain the rise in 6-TGN concentrations as HGPRT is the first enzyme, responsible for the generation of 6-TGN. Since HGPRT is also involved in formation of methylated 6-MP ribonucleotides, one would expect an increase in 6-MMPR.…”

Section: 29mentioning

confidence: 99%

“…In analogy with a previous study no difference in HGPRT activity was observed between gender and disease type (CD and UC). 31 As a classical XO inhibitor, allopurinol decreased the activity of XO after initiating allopurinol. With regard to thiopurine metabolism, decreased XO activity, either by inhibition or by a decreased activity of XO, causes less shunting towards the XO pathway, thereby increasing the concentration of 6MP that remains available for conversion into 6-TGN but theoretically also for the conversion into 6-MMPR (Fig.…”

Section: 29mentioning

confidence: 99%

The effect of allopurinol and low-dose thiopurine combination therapy on the activity of three pivotal thiopurine metabolizing enzymes: Results from a prospective pharmacological study

Seinen

Asseldonk

Boer

et al. 2013

Journal of Crohn's and Colitis

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Introduction: Thiopurine therapy is often discontinued in inflammatory bowel disease (IBD) patients. The xanthine oxidase (XO) inhibitor allopurinol has previously shown to enhance thiopurine efficacy and to prevent adverse reactions, the mechanism of this beneficial interaction is not completely clarified. The aim of this study is to observe possible effects of allopurinol and low-dose thiopurine combination therapy on the activity of three pivotal thiopurine metabolizing enzymes. Methods: A prospective study of IBD patients failing thiopurine therapy due to a skewed thiopurine metabolism was performed. Patients were treated with allopurinol and azathioprine or mercaptopurine. Xanthine oxidase, hypoxanthine-guanine phosphoribosyl transferase (HGPRT) and thiopurine S-methyl transferase (TPMT) activities, and thiopurine metabolites concentrations were measured during thiopurine monotherapy, and after 4 and 12 weeks of combination therapy. Conclusion: Allopurinol and thiopurine combination-therapy seems to increase HGPRT and decrease XO activity in IBD patients, which at least in part may explain the observed changes in thiopurine metabolite concentrations.

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Hypoxanthine guanine phosphoribosyltransferase activity is related to 6-thioguanine nucleotide concentrations and thiopurine-induced leukopenia in the treatment of inflammatory bowel disease

Abstract: High levels of HPRT activity could be a predictor of leukopenia and unsafe 6-TGN concentrations in patients undergoing AZA/6-MP therapy. This could partly explain the therapeutic response or toxicity that could not be adequately explained by the polymorphisms of TPMT.

Cited by 34 publications

References 65 publications

The impact of glutathione S–transferase genotype and phenotype on the adverse drug reactions to azathioprine in patients with inflammatory bowel diseases

The impact of glutathione S–transferase genotype and phenotype on the adverse drug reactions to azathioprine in patients with inflammatory bowel diseases

Allopurinol Enhances the Activity of Hypoxanthine-Guanine Phosphoribosyltransferase in Inflammatory Bowel Disease Patients During Low-Dose Thiopurine Therapy: Preliminary Data of an Ongoing Series

The effect of allopurinol and low-dose thiopurine combination therapy on the activity of three pivotal thiopurine metabolizing enzymes: Results from a prospective pharmacological study

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