Abstract
Background: Thiopurine antimetabolites are important agents for the treatment of severe diseases, such as acute lymphoblastic leukemia and inflammatory bowel disease. Their pharmacological actions depend on biotransformation into active thioguanine-nucleotides; intracellular metabolism is mediated by enzymes of the salvage pathway of nucleotide synthesis and relies on polymorphic enzymes involved in thiopurines' catabolism such as thiopurine-S-methyl transferase. Given the enzymes involved in thiopurines' metabolism, it is reasonable to hypothesize that these drugs are able to induce significant oxidative stress conditions, possibly altering their pharmacological activity. Methods: A systemic search of peer-reviewed scientific literature in bibliographic databases has been carried out. Both clinical and preclinical studies as well as mechanistic studies have been included to shed light on the role of oxidative stress in thiopurines' pharmacological effects. Results: Sixty-nine papers were included in our review, allowing us to review the contribution of oxidative stress in the pharmacological action of thiopurines. Thiopurines are catabolized in the liver by xanthine oxidase, with potential production of reactive oxidative species and azathioprine is converted into mercaptopurine by a reaction with reduced glutathione, that, in some tissues, may be facilitated by glutathione-S-transferase (GST). A clear role of GSTM1 in modulating azathioprine cytotoxicity, with a close dependency on superoxide anion production, has been recently demonstrated. Interestingly, recent genome-wide association studies have shown that, for both azathioprine in inflammatory bowel disease and mercaptopurine in acute lymphoblastic leukemia, treatment effects on patients' white blood cells are related to variants of a gene, NUDT15, involved in biotransformation of oxidated nucleotides. Conclusions: Basing on previous evidences published in literature, oxidative stress may contribute to thiopurine effects in significant ways that, however, are still not completely elucidated.
| Original language | English |
|---|---|
| Pages (from-to) | 542-549 |
| Number of pages | 8 |
| Journal | Current Drug Metabolism |
| Volume | 17 |
| Issue number | 6 |
| Publication status | Published - 2016 |
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Keywords
- Acute lymphoblastic leukemia
- Azathioprine
- Mercaptopurine
- Nflammatory bowel disease
- Oxidative stress
- Pharmacogenetics
- Therapy personalization
- Thioguanine
- neoplasms
ASJC Scopus subject areas
- Pharmacology
- Clinical Biochemistry
Cite this
Thiopurine biotransformation and pharmacological effects : Contribution of oxidative stress. / Pelin, Marco; De Iudicibus, Sara; Londero, Margherita; Spizzo, Riccardo; Rossi, Sveva Dei; Martelossi, Stefano; Ventura, Alessandro; Decorti, Giuliana; Stocco, Gabriele.
In: Current Drug Metabolism, Vol. 17, No. 6, 2016, p. 542-549.Research output: Contribution to journal › Review article
}
TY - JOUR
T1 - Thiopurine biotransformation and pharmacological effects
T2 - Contribution of oxidative stress
AU - Pelin, Marco
AU - De Iudicibus, Sara
AU - Londero, Margherita
AU - Spizzo, Riccardo
AU - Rossi, Sveva Dei
AU - Martelossi, Stefano
AU - Ventura, Alessandro
AU - Decorti, Giuliana
AU - Stocco, Gabriele
PY - 2016
Y1 - 2016
N2 - Background: Thiopurine antimetabolites are important agents for the treatment of severe diseases, such as acute lymphoblastic leukemia and inflammatory bowel disease. Their pharmacological actions depend on biotransformation into active thioguanine-nucleotides; intracellular metabolism is mediated by enzymes of the salvage pathway of nucleotide synthesis and relies on polymorphic enzymes involved in thiopurines' catabolism such as thiopurine-S-methyl transferase. Given the enzymes involved in thiopurines' metabolism, it is reasonable to hypothesize that these drugs are able to induce significant oxidative stress conditions, possibly altering their pharmacological activity. Methods: A systemic search of peer-reviewed scientific literature in bibliographic databases has been carried out. Both clinical and preclinical studies as well as mechanistic studies have been included to shed light on the role of oxidative stress in thiopurines' pharmacological effects. Results: Sixty-nine papers were included in our review, allowing us to review the contribution of oxidative stress in the pharmacological action of thiopurines. Thiopurines are catabolized in the liver by xanthine oxidase, with potential production of reactive oxidative species and azathioprine is converted into mercaptopurine by a reaction with reduced glutathione, that, in some tissues, may be facilitated by glutathione-S-transferase (GST). A clear role of GSTM1 in modulating azathioprine cytotoxicity, with a close dependency on superoxide anion production, has been recently demonstrated. Interestingly, recent genome-wide association studies have shown that, for both azathioprine in inflammatory bowel disease and mercaptopurine in acute lymphoblastic leukemia, treatment effects on patients' white blood cells are related to variants of a gene, NUDT15, involved in biotransformation of oxidated nucleotides. Conclusions: Basing on previous evidences published in literature, oxidative stress may contribute to thiopurine effects in significant ways that, however, are still not completely elucidated.
AB - Background: Thiopurine antimetabolites are important agents for the treatment of severe diseases, such as acute lymphoblastic leukemia and inflammatory bowel disease. Their pharmacological actions depend on biotransformation into active thioguanine-nucleotides; intracellular metabolism is mediated by enzymes of the salvage pathway of nucleotide synthesis and relies on polymorphic enzymes involved in thiopurines' catabolism such as thiopurine-S-methyl transferase. Given the enzymes involved in thiopurines' metabolism, it is reasonable to hypothesize that these drugs are able to induce significant oxidative stress conditions, possibly altering their pharmacological activity. Methods: A systemic search of peer-reviewed scientific literature in bibliographic databases has been carried out. Both clinical and preclinical studies as well as mechanistic studies have been included to shed light on the role of oxidative stress in thiopurines' pharmacological effects. Results: Sixty-nine papers were included in our review, allowing us to review the contribution of oxidative stress in the pharmacological action of thiopurines. Thiopurines are catabolized in the liver by xanthine oxidase, with potential production of reactive oxidative species and azathioprine is converted into mercaptopurine by a reaction with reduced glutathione, that, in some tissues, may be facilitated by glutathione-S-transferase (GST). A clear role of GSTM1 in modulating azathioprine cytotoxicity, with a close dependency on superoxide anion production, has been recently demonstrated. Interestingly, recent genome-wide association studies have shown that, for both azathioprine in inflammatory bowel disease and mercaptopurine in acute lymphoblastic leukemia, treatment effects on patients' white blood cells are related to variants of a gene, NUDT15, involved in biotransformation of oxidated nucleotides. Conclusions: Basing on previous evidences published in literature, oxidative stress may contribute to thiopurine effects in significant ways that, however, are still not completely elucidated.
KW - Acute lymphoblastic leukemia
KW - Azathioprine
KW - Mercaptopurine
KW - Nflammatory bowel disease
KW - Oxidative stress
KW - Pharmacogenetics
KW - Therapy personalization
KW - Thioguanine
KW - neoplasms
UR - http://www.scopus.com/inward/record.url?scp=84973861112&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84973861112&partnerID=8YFLogxK
M3 - Review article
VL - 17
SP - 542
EP - 549
JO - Current Drug Metabolism
JF - Current Drug Metabolism
SN - 1389-2002
IS - 6
ER -