ArticleChemical research in toxicology2017
The Dihydroxy Metabolite of the Teratogen Thalidomide Causes Oxidative DNA Damage.
Article in Chemical research in toxicology, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.
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Who cites it
25 citing papers in PubMed, 42 citations in OpenAlex.
- Review
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- Tumor-associated macrophages contribute to cisplatin resistance via regulating Pol η-mediated translesion DNA synthesis in ovarian cancer.Cellular and molecular life sciences : CMLS · 2025Article
- Thalidomide-induced limb malformations: an update and reevaluation.Archives of toxicology · 2025Review
- Cardiovascular Autonomic Dysfunction Before and After Chemotherapy in Cancer Patients.Journal of clinical neurology (Seoul, Korea) · 2024Review
- Formation of potentially toxic metabolites of drugs in reactions catalyzed by human drug-metabolizing enzymes.Archives of toxicology · 2024Review
- Comparison and development of machine learning for thalidomide-induced peripheral neuropathy prediction of refractory Crohn's disease in Chinese population.World journal of gastroenterology · 2023Article
- DNA damage in preimplantation embryos and gametes: specification, clinical relevance and repair strategies.Human reproduction update · 2022Review
- Genetically induced redox stress occurs in a yeast model for Roberts syndrome.G3 (Bethesda, Md.) · 2022Article
- Environmental exposures associated with elevated risk for autism spectrum disorder may augment the burden of deleterious de novo mutations among probands.Molecular psychiatry · 2022Review
- Oxidative DNA Damage: A Role in Altering Neuronal Function.Journal of cellular signaling · 2022Article
- Melittin, a honeybee venom derived peptide for the treatment of chemotherapy-induced peripheral neuropathy.Medical oncology (Northwood, London, England) · 2021Review
- Deciphering Key Interactions of Ligands with CYP3A4-Template* system.Food safety (Tokyo, Japan) · 2021Article
- Peripheral Neuropathy under Oncologic Therapies: A Literature Review on Pathogenetic Mechanisms.International journal of molecular sciences · 2021Review
- Modeling the Bioactivation and Subsequent Reactivity of Drugs.Chemical research in toxicology · 2021Article
- Chemotherapy and Radiation-Associated Cardiac Autonomic Dysfunction.Current oncology reports · 2021Review
- DNA damage by Withanone as a potential cause of liver toxicity observed for herbal products ofCurrent research in toxicology · 2021Article
- A history of the roles of cytochrome P450 enzymes in the toxicity of drugs.Toxicological research · 2021Review
- An ever-changing landscape in Roberts syndrome biology: Implications for macromolecular damage.PLoS genetics · 2020Review
Corrections and comments
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Authors and funding
6 authors at 4 institutions in 3 countries.
Funding
Abstract
Thalidomide [α-(N-phthalimido)glutarimide] (1) is a sedative and antiemetic drug originally introduced into the clinic in the 1950s for the treatment of morning sickness. Although marketed as entirely safe, more than 10 000 babies were born with severe birth defects. Thalidomide was banned and subsequently approved for the treatment of multiple myeloma and complications associated with leprosy. Although known for more than 5 decades, the mechanism of teratogenicity remains to be conclusively understood. Various theories have been proposed in the literature including DNA damage and ROS and inhibition of angiogenesis and cereblon. All of the theories have their merits and limitations. Although the recently proposed cereblon theory has gained wide acceptance, it fails to explain the metabolism and low-dose requirement reported by a number of groups. Recently, we have provided convincing structural evidence in support of the presence of arene oxide and the quinone-reactive intermediates. However, the ability of these reactive intermediates to impart toxicity/teratogenicity needs investigation. Herein we report that the oxidative metabolite of thalidomide, dihydroxythalidomide, is responsible for generating ROS and causing DNA damage. We show, using cell lines, the formation of comet (DNA damage) and ROS. Using DNA-cleavage assays, we also show that catalase, radical scavengers, and desferal are capable of inhibiting DNA damage. A mechanism of teratogenicity is proposed that not only explains the DNA-damaging property but also the metabolism, low concentration, and species-specificity requirements of thalidomide.
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