ArticleDrug metabolism and disposition: the biological fate of chemicals2014
In vitro oxidative metabolism of 6-mercaptopurine in human liver: insights into the role of the molybdoflavoenzymes aldehyde oxidase, xanthine oxidase, and xanthine dehydrogenase.
Article in Drug metabolism and disposition: the biological fate of chemicals, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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Who cites it
15 citing papers in PubMed, 37 citations in OpenAlex.
- Homeostasis of Molybdenum, Xanthine Oxidase and Aldehyde Oxidase Activity Levels in the Livers of Patients with End-Stage Liver Failure and Healthy Controls.International journal of molecular sciences · 2026Article
- RUCAM-ascertained immunology and autoimmunity specifics of six idiosyncratic drug-induced liver injury types with refined classification: their individual complex molecular interplay.Frontiers in immunology · 2026Review
- Drug-Induced Autoimmune Hepatitis by Varenicline and Infliximab as a Continuous Disease Spectrum with Two Different Flares: Acute Liver Injury Followed by Hepatic Autoimmunity.International journal of molecular sciences · 2025Review
- Variability in intestinal drug metabolizing enzymes and transporters in Crohn's disease and potential impact on oral drug absorption.British journal of clinical pharmacology · 2025Article
- Molybdenum's Role as an Essential Element in Enzymes Catabolizing Redox Reactions: A Review.Biomolecules · 2024Review
- Molecular Idiosyncratic Toxicology of Drugs in the Human Liver Compared with Animals: Basic Considerations.International journal of molecular sciences · 2023Review
- Article
- Genetic variants of genes involved in thiopurine metabolism pathway are associated with 6-mercaptopurine toxicity in pediatric acute lymphoblastic leukemia patients from Ethiopia.Frontiers in pharmacology · 2023Article
- Roles of selected non-P450 human oxidoreductase enzymes in protective and toxic effects of chemicals: review and compilation of reactions.Archives of toxicology · 2022Review
- Chloromethyl Glycosides as Versatile Synthons to Prepare Glycosyloxymethyl-Prodrugs.Chemistry (Weinheim an der Bergstrasse, Germany) · 2022Article
- Mechanism of idiosyncratic drug induced liver injury (DILI): unresolved basic issues.Annals of translational medicine · 2021Review
- Determination of Urinary Caffeine Metabolites as Biomarkers for Drug Metabolic Enzyme Activities.Nutrients · 2019Article
- Role of Molybdenum-Containing Enzymes in the Biotransformation of the Novel Ghrelin Receptor Inverse Agonist PF-5190457: A Reverse Translational Bed-to-Bench Approach.Drug metabolism and disposition: the biological fate of chemicals · 2019Article
- Revisiting the Role of Thiopurines in Inflammatory Bowel Disease Through Pharmacogenomics and Use of Novel Methods for Therapeutic Drug Monitoring.Frontiers in pharmacology · 2018Review
- Xanthine Oxidoreductase in Drug Metabolism: Beyond a Role as a Detoxifying Enzyme.Current medicinal chemistry · 2016Review
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
Abstract
Anticancer agent 6-mercaptopurine (6MP) has been in use since 1953 for the treatment of childhood acute lymphoblastic leukemia (ALL) and inflammatory bowel disease. Despite being available for 60 years, several aspects of 6MP drug metabolism and pharmacokinetics in humans are unknown. Molybdoflavoenzymes such as aldehyde oxidase (AO) and xanthine oxidase (XO) have previously been implicated in the metabolism of this drug. In this study, we investigated the in vitro metabolism of 6MP to 6-thiouric acid (6TUA) in pooled human liver cytosol. We discovered that 6MP is metabolized to 6TUA through sequential metabolism via the 6-thioxanthine (6TX) intermediate. The role of human AO and XO in the metabolism of 6MP was established using the specific inhibitors raloxifene and febuxostat. Both AO and XO were involved in the metabolism of the 6TX intermediate, whereas only XO was responsible for the conversion of 6TX to 6TUA. These findings were further confirmed using purified human AO and Escherichia coli lysate containing expressed recombinant human XO. Xanthine dehydrogenase (XDH), which belongs to the family of xanthine oxidoreductases and preferentially reduces nicotinamide adenine dinucleotide (NAD(+)), was shown to contribute to the overall production of the 6TX intermediate as well as the final product 6TUA in the presence of NAD(+) in human liver cytosol. In conclusion, we present evidence that three enzymes, AO, XO, and XDH, contribute to the production of 6TX intermediate, whereas only XO and XDH are involved in the conversion of 6TX to 6TUA in pooled HLC.
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