ArticleArchives of biochemistry and biophysics2015
The busulfan metabolite EdAG irreversibly glutathionylates glutaredoxins.
Article in Archives of biochemistry and biophysics, 2015. 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, 25 citations in OpenAlex.
- From Therapeutic Drug Monitoring to Model-Informed Precision Dosing: A Review of Busulfan Dosing Optimization in Pediatric Hematopoietic Stem Cell Transplantation.Pharmaceutics · 2026Review
- The presence of busulfan metabolites and pharmacometabolomics in plasma drawn immediately before allograft infusion in hematopoietic cell transplant recipients.Clinical and translational science · 2023Article
- Glutathione: Lights and Shadows in Cancer Patients.Biomedicines · 2023Review
- Characterization and quantitation of busulfan DNA adducts in the blood of patients receiving busulfan therapy.Molecular therapy oncolytics · 2023Article
- Antioxidant, antihyperglycemic, and antihyperlipidemic properties ofFrontiers in nutrition · 2023Article
- Glutathione-Mediated Conjugation of Anticancer Drugs: An Overview of Reaction Mechanisms and Biological Significance for Drug Detoxification and Bioactivation.Molecules (Basel, Switzerland) · 2022Review
- Population pharmacokinetic model for once-daily intravenous busulfan in pediatric subjects describing time-associated clearance.CPT: pharmacometrics & systems pharmacology · 2022Article
- Review of the Pharmacokinetics and Pharmacodynamics of Intravenous Busulfan in Paediatric Patients.Clinical pharmacokinetics · 2021Review
- A mouse model of subacute liver failure with ascites induced by step-wise increased doses of (-)-epigallocatechin-3-gallate.Scientific reports · 2019Article
- Glutathione transferases: substrates, inihibitors and pro-drugs in cancer and neurodegenerative diseases.Oncogenesis · 2018Review
- Clarifying busulfan metabolism and drug interactions to support new therapeutic drug monitoring strategies: a comprehensive review.Expert opinion on drug metabolism & toxicology · 2017Review
- The Association of CombinedFrontiers in pharmacology · 2017Article
- Article
- The Myeloablative Drug Busulfan Converts Cysteine to Dehydroalanine and Lanthionine in Redoxins.Biochemistry · 2016Article
- Supporting data for characterization of the busulfan metabolite EdAG and the Glutaredoxins that it adducts.Data in brief · 2015Article
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Authors and funding
2 authors at 1 institution in 1 country.
Funding
Abstract
The DNA alkylating agent busulfan is used to 'precondition' patients with leukemia, lymphomas and other hematological disorders prior to hematopoietic stem cell transplants. Busulfan is metabolized via conjugation with glutathione (GSH) followed by intramolecular rearrangement to the GSH analog γ-glutamyl-dehydroalanyl -glycine (EdAG). EdAG contains the electrophilic dehydroalanine, which is expected to react with protein nucleophiles, particularly proteins with GSH binding sites such as glutaredoxins (Grx's). Incubation of EdAG with human Grx-1 or Grx-2 results in facile adduction of cys-23 and cys-77, respectively, as determined by ESI-MS/MS. The resulting modified proteins are catalytically inactive. In contrast, the glutathione transferase A1-1 includes a GSH binding site with a potentially reactive tyrosinate (Tyr-9) but it does not react with EdAG. Similarly, Cys-112 of GSTA1-1, which lies outside the active site and is known to form disulfides with GSH, does not react with EdAG. The results provide the first demonstration of the reactivity of any busulfan metabolites with intact proteins, and they suggest that GSH-binding sites containing thiolates are most susceptible. The adduction of Grx's by EdAG suggests the possible alteration of proteins that are normally regulated via Grx-dependent reversible glutathionylation or deglutathionylation. Dysregulation of Grx-dependent processes could contribute to cellular toxicity of busulfan.
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