ArticleChemical research in toxicology2018
Cytochromes P450 1A2 and 3A4 Catalyze the Metabolic Activation of Sunitinib.
Article in Chemical research in toxicology, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 37 papers, 1 of them a synthesis that pooled it.
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Who cites it
37 citing papers in PubMed, 1 synthesis or guideline pooled it, 81 citations in OpenAlex.
- Comparison of Hepatotoxicity Associated With New BCR-ABL Tyrosine Kinase Inhibitors vs Imatinib Among Patients With Chronic Myeloid Leukemia: A Systematic Review and Meta-analysis.JAMA network open · 2021Pooled it
- Assessing Fluoroacetate Defluorination Potential across Diverse Enzymes Using Quantum Chemistry.The journal of physical chemistry. B · 2026Article
- Evaluation of QTc interval prolongation in patients with advanced clear cell renal cell carcinoma treated with first line sunitinib.Cancer chemotherapy and pharmacology · 2026Article
- Elucidating the binding and metabolic interactions of sunitinib and sorafenib with Cytochrome P450s CYP2U1 and CYP2D6.Molecular pharmacology · 2026Article
- Discovery of Lenacapavir: First-in-Class Twice-Yearly Capsid Inhibitor for HIV-1 Treatment and Pre-exposure Prophylaxis.Journal of medicinal chemistry · 2025Article
- Computational Studies of Enzymes for C-F Bond Degradation and Functionalization.Chemphyschem : a European journal of chemical physics and physical chemistry · 2025Review
- Review
- Strategy for cysteine-targeting covalent inhibitors screening using in-house database based LC-MS/MS and drug repurposing.Journal of pharmaceutical analysis · 2025Article
- Human Cytochrome P450 Cancer-Related Metabolic Activities and Gene Polymorphisms: A Review.Cells · 2024Review
- Preclinical evaluation of anEJNMMI radiopharmacy and chemistry · 2024Article
- A real-world pharmacovigilance study of FDA adverse event reporting system (FAERS) events for sunitinib.Frontiers in pharmacology · 2024Article
- Simultaneously discovering the fate and biochemical effects of pharmaceuticals through untargeted metabolomics.Nature communications · 2023Article
- The role of cytochrome P450 3A4-mediated metabolism in sorafenib and lapatinib hepatotoxicity.Livers · 2023Article
- Mechanisms of tyrosine kinase inhibitor resistance in renal cell carcinoma.Cancer drug resistance (Alhambra, Calif.) · 2023Review
- Cytochromes P450 2C8 and 3A Catalyze the Metabolic Activation of the Tyrosine Kinase Inhibitor Masitinib.Chemical research in toxicology · 2022Article
- Biological Role of Pazopanib and Sunitinib Aldehyde Derivatives in Drug-Induced Liver Injury.Metabolites · 2022Article
- The transient-chelating-group-controlled stereoselective Rh(i)-catalyzed silylative aminocarbonylation of 2-alkynylanilines: access to (Chemical science · 2022Article
- Interindividual Variability in Cytochrome P450 3A and 1A Activity Influences Sunitinib Metabolism and Bioactivation.Chemical research in toxicology · 2022Article
- Severe tyrosine-kinase inhibitor induced liver injury in metastatic renal cell carcinoma patients: two case reports assessed for causality using the updated RUCAM and review of the literature.BMC gastroenterology · 2022Review
- Absorption, Metabolism, and Excretion of ACT-1004-1239, a First-In-Class CXCR7 Antagonist:Frontiers in pharmacology · 2022Article
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10 authors at 1 institution in 1 country.
Funding
Abstract
Sunitinib is a multitargeted tyrosine kinase inhibitor associated with idiosyncratic hepatotoxicity. The mechanisms of this toxicity are unknown. We hypothesized that sunitinib undergoes metabolic activation to form chemically reactive, potentially toxic metabolites which may contribute to development of sunitinib-induced hepatotoxicity. The purpose of this study was to define the role of cytochrome P450 (P450) enzymes in sunitinib bioactivation. Metabolic incubations were performed using individual recombinant P450s, human liver microsomal fractions, and P450-selective chemical inhibitors. Glutathione (GSH) and dansylated GSH were used as trapping agents to detect reactive metabolite formation. Sunitinib metabolites were analyzed by liquid chromatography-tandem mass spectrometry. A putative quinoneimine-GSH conjugate (M5) of sunitinib was detected from trapping studies with GSH and dansyl-GSH in human liver microsomal incubations, and M5 was formed in an NADPH-dependent manner. Recombinant P450 1A2 generated the highest levels of defluorinated sunitinib (M3) and M5, with less formation by P450 3A4 and 2D6. P450 3A4 was the major enzyme forming the primary active metabolite N-desethylsunitinib (M1). In human liver microsomal incubations, P450 3A inhibitor ketoconazole reduced formation of M1 by 88%, while P450 1A2 inhibitor furafylline decreased generation of M5 by 62% compared to control levels. P450 2D6 and P450 3A inhibition also decreased M5 by 54 and 52%, respectively, compared to control. In kinetic assays, recombinant P450 1A2 showed greater efficiency for generation of M3 and M5 compared to that of P450 3A4 and 2D6. Moreover, M5 formation was 2.7-fold more efficient in human liver microsomal preparations from an individual donor with high P450 1A2 activity compared to a donor with low P450 1A2 activity. Collectively, these data suggest that P450 1A2 and 3A4 contribute to oxidative defluorination of sunitinib to generate a reactive, potentially toxic quinoneimine. Factors that alter P450 1A2 and 3A activity may affect patient risk for sunitinib toxicity.
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