Exploring the role of oxidative stress and the effect of N-acetylcysteine in thiopurine-induced liver injury in inflammatory bowel disease: A randomized crossover pilot study.

Nanne K de Boer, Peter G Scheffer, Margien L Seinen, Godefridus J Peters, Adriaan A van Bodegraven, Dirk P van Asseldonk, Femke Crouwel, Agnes I Veldkamp, Birgit Lissenberg-Witte

Journal: Basic & clinical pharmacology & toxicology 2024;134(4):507-518

PMID: 38284479

Free Full Text on Wiley View on PubMed

Abstract

Thiopurine treatment is regularly complicated by drug-induced liver injury. It has been suggested that oxidative stress may play a synergistic role. To assess whether thiopurine-induced liver injury coincides with increased oxidative stress and whether co-administration with N-acetylcysteine is protective, we performed a randomized open label crossover pilot study in inflammatory bowel disease patients with thiopurine-induced increased serum liver tests. The study comprised four stages of 4 weeks. Patients received no additional therapy followed by N-acetylcysteine 1200 mg twice a day, or the other way around, alongside ongoing thiopurine treatment. The third and fourth stages comprised a washout period and thiopurine reintroduction period. Nine patients completed the study, and the addition of N-acetylcysteine decreased myeloperoxidase concentrations (33.6-24.5 pmol/L, p = 0.038). The other biomarkers remained unchanged, including thiopurine metabolites, xanthine oxidase activity, thiopurine S-methyltransferase activity and serum liver enzyme activity tests. Reintroduction of thiopurines led to an increase of F2-isoprostanes (101-157 ng/mmol, p = 0.038), but not of serum liver enzyme activity tests. Results suggests that thiopurines may increase oxidative stress and although the addition of N-acetylcysteine led to a decrease in plasma myeloperoxidase concentrations, it does not protect from thiopurine-induced increase of serum liver tests.

Address: Department of Gastroenterology and Hepatology, Noordwest Ziekenhuisgroep, Alkmaar, The Netherlands.; Department of Gastroenterology and Hepatology, Amsterdam Gastroenterology Endocrinology Metabolism Research Institute, Amsterdam University Medical Centers, Location VUMC, Amsterdam, The Netherlands.; Department of Gastroenterology and Hepatology, Amsterdam Gastroenterology Endocrinology Metabolism Research Institute, Amsterdam University Medical Centers, Location VUMC, Amsterdam, The Netherlands.; Department of Gastroenterology and Hepatology, Amsterdam Gastroenterology Endocrinology Metabolism Research Institute, Amsterdam University Medical Centers, Location VUMC, Amsterdam, The Netherlands.; Department of Gastroenterology and Hepatology, Onze Lieve Vrouwe Gasthuis, Amsterdam, The Netherlands.; Metabolic Laboratory, Department of Clinical Chemistry, Amsterdam University Medical Centers, Location VUMC, Amsterdam, The Netherlands.; Department of Clinical Pharmacology and Pharmacy, Amsterdam University Medical Centers, Location VUMC, Amsterdam, The Netherlands.; Department of Epidemiology and Data Science, Amsterdam University Medical Centers, Location VUMC, Amsterdam, The Netherlands.; Department of Medical Oncology, Amsterdam University Medical Centers, Location VUMC, Amsterdam, The Netherlands.; Department of Biochemistry, Medical University of Gdansk, Gdansk, Poland.; Department of Gastroenterology and Hepatology, Amsterdam Gastroenterology Endocrinology Metabolism Research Institute, Amsterdam University Medical Centers, Location VUMC, Amsterdam, The Netherlands.; Department of Gastroenterology, Geriatrics, Internal and Intensive Care Medicine (CO-MIK), Zuyderland Medical Centre, Heerlen-Sittard-Geleen, The Netherlands.

DOI: 10.1111/bcpt.13978