Alpha-Lipoic Acid and Its Enantiomers Prevent Methemoglobin Formation and DNA Damage Induced by Dapsone Hydroxylamine: Molecular Mechanism and Antioxidant Action

Int J Mol Sci. 2022 Dec 21;24(1):57. doi: 10.3390/ijms24010057.

Abstract

Dapsone (DDS) therapy can frequently lead to hematological side effects, such as methemoglobinemia and DNA damage. In this study, we aim to evaluate the protective effect of racemic alpha lipoic acid (ALA) and its enantiomers on methemoglobin induction. The pre- and post-treatment of erythrocytes with ALA, ALA isomers, or MB (methylene blue), and treatment with DDS-NOH (apsone hydroxylamine) was performed to assess the protective and inhibiting effect on methemoglobin (MetHb) formation. Methemoglobin percentage and DNA damage caused by dapsone and its metabolites were also determined by the comet assay. We also evaluated oxidative parameters such as SOD, GSH, TEAC (Trolox equivalent antioxidant capacity) and MDA (malondialdehyde). In pretreatment, ALA showed the best protector effect in 2.5 µg/mL of DDS-NOH. ALA (1000 µM) was able to inhibit the induced MetHb formation even at the highest concentrations of DDS-NOH. All ALA tested concentrations (100 and 1000 µM) were able to inhibit ROS and CAT activity, and induced increases in GSH production. ALA also showed an effect on DNA damage induced by DDS-NOH (2.5 µg/mL). Both isomers were able to inhibit MetHb formation and the S-ALA was able to elevate GSH levels by stimulating the production of this antioxidant. In post-treatment with the R-ALA, this enantiomer inhibited MetHb formation and increased GSH levels. The pretreatment with R-ALA or S-ALA prevented the increase in SOD and decrease in TEAC, while R-ALA decreased the levels of MDA; and this pretreatment with R-ALA or S-ALA showed the effect of ALA enantiomers on DNA damage. These data show that ALA can be used in future therapies in patients who use dapsone chronically, including leprosy patients.

Keywords: DNA damage; alpha lipoic acid; dapsone.

MeSH terms

  • Antioxidants / pharmacology
  • DNA Damage
  • Dapsone / pharmacology
  • Methemoglobin* / metabolism
  • Superoxide Dismutase
  • Thioctic Acid* / pharmacology

Substances

  • Methemoglobin
  • Antioxidants
  • 4-amino-4'-hydroxylaminodiphenylsulfone
  • Thioctic Acid
  • Dapsone
  • Superoxide Dismutase

Grants and funding

This research was funded by the conselho nacional de desenvolvimento científico e tecnológico (CNPQ), the coordenação de aperfeiçoamento de pessoal de nível superior (CAPES), the fundação amazônia paraense de amparo à pesquisa (FAPESPA) and the federal university of pará (UFPA). In addition, we thank the programa de apoio à pós graduação coordenação de aperfeiçoamento de pessoal de nível superior (CAPES) by procad for financial support. This work was also supported by the pró-reitoria de pesquisa e pós-graduação da ufpa (propesp, ufpa, brazil) on open access publication fees. MCM are supported by a research fellowship from cnpq.