ArticleChemical research in toxicology2014
Human cytochrome P450 oxidation of 5-hydroxythalidomide and pomalidomide, an amino analogue of thalidomide.
Article in Chemical research in toxicology, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed, 35 citations in OpenAlex.
- Thalidomide-induced limb malformations: an update and reevaluation.Archives of toxicology · 2025Review
- Construction of a CYP2J2-Template System and Its Application for Ligand Metabolism Prediction.Food safety (Tokyo, Japan) · 2024Article
- Formation of potentially toxic metabolites of drugs in reactions catalyzed by human drug-metabolizing enzymes.Archives of toxicology · 2024Review
- Article
- Characterization of Clofazimine Metabolism in Human Liver Microsomal IncubationAntimicrobial agents and chemotherapy · 2022Article
- Nontargeted Metabolomics by High-Resolution Mass Spectrometry to Study the In Vitro Metabolism of a Dual Inverse Agonist of Estrogen-Related Receptors β and γ, DN203368.Pharmaceutics · 2021Article
- A history of the roles of cytochrome P450 enzymes in the toxicity of drugs.Toxicological research · 2021Review
- DNA damage by Withanone as a potential cause of liver toxicity observed for herbal products ofCurrent research in toxicology · 2021Article
- An ever-changing landscape in Roberts syndrome biology: Implications for macromolecular damage.PLoS genetics · 2020Review
- Structural bases of IMiD selectivity that emerges by 5-hydroxythalidomide.Nature communications · 2020Article
- Development of a physiologically based pharmacokinetic model for intravenous lenalidomide in mice.Cancer chemotherapy and pharmacology · 2019Article
- Association of pharmacokinetic profiles of lenalidomide in human plasma simulated using pharmacokinetic data in humanized-liver mice with liver toxicity detected by human serum albumin RNA.The Journal of toxicological sciences · 2018Article
- Metabolic profiles of pomalidomide in human plasma simulated with pharmacokinetic data in control and humanized-liver mice.Xenobiotica; the fate of foreign compounds in biological systems · 2017Article
- The Dihydroxy Metabolite of the Teratogen Thalidomide Causes Oxidative DNA Damage.Chemical research in toxicology · 2017Article
- Formation and Biological Targets of Quinones: Cytotoxic versus Cytoprotective Effects.Chemical research in toxicology · 2017Article
- Induction of human cytochrome P450 3A enzymes in cultured placental cells by thalidomide and relevance to bioactivation and toxicity.The Journal of toxicological sciences · 2017Article
- Combining Chimeric Mice with Humanized Liver, Mass Spectrometry, and Physiologically-Based Pharmacokinetic Modeling in Toxicology.Chemical research in toxicology · 2016Review
- Assessment of Protein Binding of 5-Hydroxythalidomide Bioactivated in Humanized Mice with Human P450 3A-Chromosome or Hepatocytes by Two-Dimensional Electrophoresis/Accelerator Mass Spectrometry.Chemical research in toxicology · 2016Article
- Simulation of Human Plasma Concentrations of Thalidomide and Primary 5-Hydroxylated Metabolites Explored with Pharmacokinetic Data in Humanized TK-NOG Mice.Chemical research in toxicology · 2015Article
- Self-disproportionation of enantiomers of thalidomide and its fluorinated analogueChemical science · 2015Article
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Authors and funding
4 authors at 2 institutions in 2 countries.
Funding
Abstract
The sedative and antiemetic drug thalidomide [α-(N-phthalimido)glutarimide] was withdrawn in the early 1960s because of its potent teratogenic effects but was approved for the treatment of lesions associated with leprosy in 1998 and multiple myeloma in 2006. The mechanism of teratogenicity of thalidomide still remains unclear, but it is well-established that metabolism of thalidomide is important for both teratogenicity and cancer treatment outcome. Thalidomide is oxidized by various cytochrome P450 (P450) enzymes, the major one being P450 2C19, to 5-hydroxy-, 5'-hydroxy-, and dihydroxythalidomide. We previously reported that P450 3A4 oxidizes thalidomide to the 5-hydroxy and dihydroxy metabolites, with the second oxidation step involving a reactive intermediate, possibly an arene oxide, that can be trapped by glutathione (GSH) to GSH adducts. We now show that the dihydroxythalidomide metabolite can be further oxidized to a quinone intermediate. Human P450s 2J2, 2C18, and 4A11 were also found to oxidize 5-hydroxythalidomide to dihydroxy products. Unlike P450s 2C19 and 3A4, neither P450 2J2, 2C18, nor 4A11 oxidized thalidomide itself. A recently approved amino analogue of thalidomide, pomalidomide (CC-4047, Actimid), was also oxidized by human liver microsomes and P450s 2C19, 3A4, and 2J2 to the corresponding phthalimide ring-hydroxylated product.
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