α-Lipoic Acid and Deferoxamine Restore Redox–Metallomic Homeostasis in Dapsone Toxicity: Integrated Biochemical, Histological, and Molecular Modeling Evidence
- 1Federal University of Pará , , , ,
- 2Laboratory of Chemical Analysis of the Museu Paraense Emílio Goeldi , , ,
Abstract
Dapsone (DDS), a sulfone antibiotic widely used in the treatment of leprosy and autoimmune diseases, is associated with hematotoxicity and hepatotoxicity due to its metabolic conversion into hydroxylamine derivatives that promote methemoglobinemia, iron dysregulation, oxidative stress, and tissue injury. In addition to CYP-mediated bioactivation, DDS may contribute to lysosomal stress-associated iron imbalance and oxidative propagation. Conventional antioxidants or iron-chelating therapies alone may provide only partial protection against these interconnected mechanisms. This study evaluated the protective effects of α-lipoic acid (ALA) and deferoxamine (DFO), administered individually or in combination, against DDS-induced oxidative and hematological disturbances using integrated in vivo and in silico approaches. Male Swiss mice received DDS (40 mg/kg, gavage) for 5 days, followed by treatment with ALA (25 mg/kg, gavage), DFO (40 mg/kg, i.p.), or their combination for an additional 5 days. Methemoglobin (MetHb), reduced glutathione (GSH), nitric oxide (NO), malondialdehyde (MDA), and plasma iron levels were evaluated. Histopathological analysis and molecular docking studies involving cytochrome P450 isoforms (CYP2C9, CYP2C19, CYP3A4, and CYP2E1) and hemoglobin were performed to investigate potential mechanisms underlying DDS-induced toxicity and the protective effects of ALA and DFO. DDS markedly increased MetHb, nitric oxide, malondialdehyde, and plasma iron levels, accompanied by depletion of GSH and hepatocellular degeneration. ALA and DFO individually attenuated oxidative and iron-related disturbances, whereas combined treatment effectively reduced methemoglobin formation and preserved hepatic architecture; however, plasma ferric iron levels remained comparable to those in DDS-treated animals. Molecular docking suggested preferential interactions of DDS with CYP2E1 and CYP3A4, supporting the biological plausibility of their involvement in oxidative bioactivation pathways, whereas DFO showed predicted interactions with CYP2C9, CYP2E1, and hemoglobin-associated iron sites. Collectively, these findings indicate that ALA and DFO each attenuate DDS-induced hepatotoxicity and hematotoxicity through distinct but complementary antioxidant, iron-chelating, and redox-modulating mechanisms. Combined treatment effectively improved selected endpoints, including methemoglobin formation and hepatic architecture, although its protective effects were endpoint-dependent. The molecular modeling results provide supportive mechanistic insights and should be interpreted as hypothesis-generating evidence complementary to the in vivo findings.
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BibTeX
@article{silva2026αlipoic,
title = {{α-Lipoic Acid and Deferoxamine Restore Redox–Metallomic Homeostasis in Dapsone Toxicity: Integrated Biochemical, Histological, and Molecular Modeling Evidence}},
author = {Rana Karen Mesquita da Silva and Amanda Caroline dos Santos Monteiro and Sara Kerolim Figueiredo Freitas and Ana Paula Holanda Santana and Kelly Davis and Wenddy Graziela Neves Lima and Pamela Suelen da Silva Seabra and Daniele Ferreira Sodré and Cristine Bastos do Amarante and Agnaldo da Silva Carneiro and Alessandro Quaresma Durães de Sousa and Savio Monteiro dos Santos and Antônio Rafael Quadros Gomes and Bruno Alexandre Quadros Gomes and Roseane Guimarães Ferreira and Marta Chagas Monteiro},
journal = {ACS Omega},
year = {2026},
month = oct,
doi = {10.1021/acsomega.6c03045},
url = {https://pubs.acs.org/acsodf/article/11/41/62581/5444816/Lipoic-Acid-and-Deferoxamine-Restore-Redox},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - α-Lipoic Acid and Deferoxamine Restore Redox–Metallomic Homeostasis in Dapsone Toxicity: Integrated Biochemical, Histological, and Molecular Modeling Evidence
AU - Rana Karen Mesquita da Silva
AU - Amanda Caroline dos Santos Monteiro
AU - Sara Kerolim Figueiredo Freitas
AU - Ana Paula Holanda Santana
AU - Kelly Davis
AU - Wenddy Graziela Neves Lima
AU - Pamela Suelen da Silva Seabra
AU - Daniele Ferreira Sodré
AU - Cristine Bastos do Amarante
AU - Agnaldo da Silva Carneiro
AU - Alessandro Quaresma Durães de Sousa
AU - Savio Monteiro dos Santos
AU - Antônio Rafael Quadros Gomes
AU - Bruno Alexandre Quadros Gomes
AU - Roseane Guimarães Ferreira
AU - Marta Chagas Monteiro
PY - 2026
DA - 2026/10/05
JO - ACS Omega
DO - 10.1021/acsomega.6c03045
UR - https://pubs.acs.org/acsodf/article/11/41/62581/5444816/Lipoic-Acid-and-Deferoxamine-Restore-Redox
AB - Dapsone (DDS), a sulfone antibiotic widely used in the treatment of leprosy and autoimmune diseases, is associated with hematotoxicity and hepatotoxicity due to its metabolic conversion into hydroxylamine derivatives that promote methemoglobinemia, iron dysregulation, oxidative stress, and tissue injury. In addition to CYP-mediated bioactivation, DDS may contribute to lysosomal stress-associated iron imbalance and oxidative propagation. Conventional antioxidants or iron-chelating therapies alone may provide only partial protection against these interconnected mechanisms. This study evaluated the protective effects of α-lipoic acid (ALA) and deferoxamine (DFO), administered individually or in combination, against DDS-induced oxidative and hematological disturbances using integrated in vivo and in silico approaches. Male Swiss mice received DDS (40 mg/kg, gavage) for 5 days, followed by treatment with ALA (25 mg/kg, gavage), DFO (40 mg/kg, i.p.), or their combination for an additional 5 days. Methemoglobin (MetHb), reduced glutathione (GSH), nitric oxide (NO), malondialdehyde (MDA), and plasma iron levels were evaluated. Histopathological analysis and molecular docking studies involving cytochrome P450 isoforms (CYP2C9, CYP2C19, CYP3A4, and CYP2E1) and hemoglobin were performed to investigate potential mechanisms underlying DDS-induced toxicity and the protective effects of ALA and DFO. DDS markedly increased MetHb, nitric oxide, malondialdehyde, and plasma iron levels, accompanied by depletion of GSH and hepatocellular degeneration. ALA and DFO individually attenuated oxidative and iron-related disturbances, whereas combined treatment effectively reduced methemoglobin formation and preserved hepatic architecture; however, plasma ferric iron levels remained comparable to those in DDS-treated animals. Molecular docking suggested preferential interactions of DDS with CYP2E1 and CYP3A4, supporting the biological plausibility of their involvement in oxidative bioactivation pathways, whereas DFO showed predicted interactions with CYP2C9, CYP2E1, and hemoglobin-associated iron sites. Collectively, these findings indicate that ALA and DFO each attenuate DDS-induced hepatotoxicity and hematotoxicity through distinct but complementary antioxidant, iron-chelating, and redox-modulating mechanisms. Combined treatment effectively improved selected endpoints, including methemoglobin formation and hepatic architecture, although its protective effects were endpoint-dependent. The molecular modeling results provide supportive mechanistic insights and should be interpreted as hypothesis-generating evidence complementary to the in vivo findings.
SN - 2470-1343
ER -