Abstract
Azathioprine (AZA), 6-mercaptopurine (6-MP), and 6-thioguanine (6-TG) are antimetabolite drugs, widely used as immunosuppressants and anticancer agents. Despite their proven efficacy, a high incidence of toxic effects in patients during standard-dose therapy is recorded. The aim of this study is to explain, from a mechanistic point of view, the clinical evidence showing a significant role of glutathione-S-transferase (GST)-M1 genotype on AZA toxicity in inflammatory bowel disease patients. To this aim, the human nontumor IHH and HCEC cell lines were chosen as predictive models of the hepatic and intestinal tissues, respectively. AZA, but not 6-MP and 6-TG, induced a concentration-dependent superoxide anion production that seemed dependent on GSH depletion. N-Acetylcysteine reduced the AZA antiproliferative effect in both cell lines, and GST-M1 overexpression increased both superoxide anion production and cytotoxicity, especially in transfected HCEC cells. In this study, an in vitro model to study thiopurines' metabolism has been set up and helped us to demonstrate, for the first time, a clear role of GST-M1 in modulating AZA cytotoxicity, with a close dependency on superoxide anion production. These results provide the molecular basis to shed light on the clinical evidence suggesting a role of GST-M1 genotype in influencing the toxic effects of AZA treatment.
| Original language | English |
|---|---|
| Pages (from-to) | 1186-1195 |
| Number of pages | 10 |
| Journal | Chemical Research in Toxicology |
| Volume | 28 |
| Issue number | 6 |
| DOIs | |
| Publication status | Published - Jun 15 2015 |
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ASJC Scopus subject areas
- Toxicology
Cite this
Role of Oxidative Stress Mediated by Glutathione-S-transferase in Thiopurines' Toxic Effects. / Pelin, Marco; De Iudicibus, Sara; Fusco, Laura; Taboga, Eleonora; Pellizzari, Giulia; Lagatolla, Cristina; Martelossi, Stefano; Ventura, Alessandro; Decorti, Giuliana; Stocco, Gabriele.
In: Chemical Research in Toxicology, Vol. 28, No. 6, 15.06.2015, p. 1186-1195.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Role of Oxidative Stress Mediated by Glutathione-S-transferase in Thiopurines' Toxic Effects
AU - Pelin, Marco
AU - De Iudicibus, Sara
AU - Fusco, Laura
AU - Taboga, Eleonora
AU - Pellizzari, Giulia
AU - Lagatolla, Cristina
AU - Martelossi, Stefano
AU - Ventura, Alessandro
AU - Decorti, Giuliana
AU - Stocco, Gabriele
PY - 2015/6/15
Y1 - 2015/6/15
N2 - Azathioprine (AZA), 6-mercaptopurine (6-MP), and 6-thioguanine (6-TG) are antimetabolite drugs, widely used as immunosuppressants and anticancer agents. Despite their proven efficacy, a high incidence of toxic effects in patients during standard-dose therapy is recorded. The aim of this study is to explain, from a mechanistic point of view, the clinical evidence showing a significant role of glutathione-S-transferase (GST)-M1 genotype on AZA toxicity in inflammatory bowel disease patients. To this aim, the human nontumor IHH and HCEC cell lines were chosen as predictive models of the hepatic and intestinal tissues, respectively. AZA, but not 6-MP and 6-TG, induced a concentration-dependent superoxide anion production that seemed dependent on GSH depletion. N-Acetylcysteine reduced the AZA antiproliferative effect in both cell lines, and GST-M1 overexpression increased both superoxide anion production and cytotoxicity, especially in transfected HCEC cells. In this study, an in vitro model to study thiopurines' metabolism has been set up and helped us to demonstrate, for the first time, a clear role of GST-M1 in modulating AZA cytotoxicity, with a close dependency on superoxide anion production. These results provide the molecular basis to shed light on the clinical evidence suggesting a role of GST-M1 genotype in influencing the toxic effects of AZA treatment.
AB - Azathioprine (AZA), 6-mercaptopurine (6-MP), and 6-thioguanine (6-TG) are antimetabolite drugs, widely used as immunosuppressants and anticancer agents. Despite their proven efficacy, a high incidence of toxic effects in patients during standard-dose therapy is recorded. The aim of this study is to explain, from a mechanistic point of view, the clinical evidence showing a significant role of glutathione-S-transferase (GST)-M1 genotype on AZA toxicity in inflammatory bowel disease patients. To this aim, the human nontumor IHH and HCEC cell lines were chosen as predictive models of the hepatic and intestinal tissues, respectively. AZA, but not 6-MP and 6-TG, induced a concentration-dependent superoxide anion production that seemed dependent on GSH depletion. N-Acetylcysteine reduced the AZA antiproliferative effect in both cell lines, and GST-M1 overexpression increased both superoxide anion production and cytotoxicity, especially in transfected HCEC cells. In this study, an in vitro model to study thiopurines' metabolism has been set up and helped us to demonstrate, for the first time, a clear role of GST-M1 in modulating AZA cytotoxicity, with a close dependency on superoxide anion production. These results provide the molecular basis to shed light on the clinical evidence suggesting a role of GST-M1 genotype in influencing the toxic effects of AZA treatment.
UR - http://www.scopus.com/inward/record.url?scp=84935897107&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84935897107&partnerID=8YFLogxK
U2 - 10.1021/acs.chemrestox.5b00019
DO - 10.1021/acs.chemrestox.5b00019
M3 - Article
C2 - 25928802
AN - SCOPUS:84935897107
VL - 28
SP - 1186
EP - 1195
JO - Chemical Research in Toxicology
JF - Chemical Research in Toxicology
SN - 0893-228X
IS - 6
ER -