Alpha-Lipoic Acid Reduces Methemoglobin and Oxidative Imbalance in the Blood and Liver Induced by Dapsone in Mice: Molecular Mechanism of Antioxidant Action

Dapsone (DDS) is a sulfone clinically used in the treatment of dermatological disorders, such as dermatitis herpetiformis and psoriasis, besides Toxoplasma gondii, Pneumocystis carinii, and Mycobacterium leprae infections. However, the chronic use of DDS can lead to adverse effects involving all organ systems, such as dapsone hypersensitivity syndrome, methemoglobinemia, hemolytic anemia, and liver injury. These effects probably occur due to the presence of its toxic metabolite DDS-NOH, which can generate reactive oxygen species (ROS), and iron overload, causing oxidative stress. In this sense, antioxidant compounds with chelating properties such as Alpha-lipoic acid (ALA) may be an interesting adjuvant therapy strategy in treating or preventing oxidative stress and adverse reactions related to DDS. This study showed that DDS 40 mg/kg increased the methemoglobin and induced oxidative stress in the erythrocytes and liver of mice. However, post-treatment with ALA 12.5 mg/kg was able to restore redox status and hepatic biomarkers in DDS-intoxicated animals. Thus, inhibiting the formation of methemoglobin and lipid peroxidation in the blood, as well as reducing iron accumulation and production of hepatic enzymes stimulated by DDS metabolism. In addition, the molecular docking shows that ALA in its oxidized form can inhibit DDS-NOH. These findings highlight the potential of ALA and its thiol derivatives as antioxidants in counteracting the harmful effects of DDS metabolites. However, further investigations are necessary to understand the therapeutic potential and antioxidant mechanisms of ALA and its derivatives for the development of new strategies to prevent or alleviate oxidative damage associated with DDS treatment.