Clinical oxidative stress during leprosy multidrug therapy: impact of dapsone oxidation.
This study aims to assess the oxidative stress in leprosy patients under multidrug therapy (MDT; dapsone, clofazimine and rifampicin), evaluating the nitric oxide (NO) concentration, catalase (CAT) and superoxide dismutase (SOD) activities, glutathione (GSH) levels, total antioxidant capacity, lipid peroxidation, and methemoglobin formation. For this, we analyzed 23 leprosy patients and 20 healthy individuals from the Amazon region, Brazil, aged between 20 and 45 years. Blood sampling enabled the evaluation of leprosy patients prior to starting multidrug therapy (called MDT 0) and until the third month of multidrug therapy (MDT 3). With regard to dapsone (DDS) plasma levels, we showed that there was no statistical difference in drug plasma levels between multibacillary (0.518±0.029 µg/mL) and paucibacillary (0.662±0.123 µg/mL) patients. The methemoglobin levels and numbers of Heinz bodies were significantly enhanced after the third MDT-supervised dose, but this treatment did not significantly change the lipid peroxidation and NO levels in these leprosy patients. In addition, CAT activity was significantly reduced in MDT-treated leprosy patients, while GSH content was increased in these patients. However, SOD and Trolox equivalent antioxidant capacity levels were similar in patients with and without treatment. These data suggest that MDT can reduce the activity of some antioxidant enzyme and influence ROS accumulation, which may induce hematological changes, such as methemoglobinemia in patients with leprosy. We also explored some redox mechanisms associated with DDS and its main oxidative metabolite DDS-NHOH and we explored the possible binding of DDS to the active site of CYP2C19 with the aid of molecular modeling software.
Laboratório de Microbiologia e Imunologia Clínica/UFPA and Programa de Pós-graduação em Ciências Farmacêuticas, Faculdade de Farmácia, Universidade Federal do Pará/UFPA, Rua Augusto Corrêa, Belém, Brasil.
Taysa Ribeiro
TR
Schalcher
Laboratório de Microbiologia e Imunologia Clínica/UFPA and Programa de Pós-graduação em Ciências Farmacêuticas, Faculdade de Farmácia, Universidade Federal do Pará/UFPA, Rua Augusto Corrêa, Belém, Brasil.
Rosivaldo S
RS
Borges
Mechanisms of Drug Toxicity Group, Department of Pharmaceutical Sciences, Aston University, Aston Triangle, Birmingham, United Kingdom.
Michael D
MD
Coleman
Centro Universitário do Distrito Federal - UDF, SEP/SUL EQ 704/904 - CONJ A, Brasília/DF, Brasil.
João
J
Batista Júnior
Laboratório de Dermato-Imunologia UFPA/MC, Marituba, Pará, and Programa de Pós-graduação em Neurociências e Biologia Celular, Instituto de Ciências Biológicas, Universidade Federal do Pará/UFPA, Bairro Guamá, Belém, Brasil.
Claudio G
CG
Salgado
Laboratório de Microbiologia e Imunologia Clínica/UFPA and Programa de Pós-graduação em Ciências Farmacêuticas, Faculdade de Farmácia, Universidade Federal do Pará/UFPA, Rua Augusto Corrêa, Belém, Brasil.
Jose Luiz F
JL
Vieira
Programa de Pós-graduação em Ciências da Saúde. Universidade Federal de Ciências da Saúde de Porto Alegre, Porto Alegre, Brasil.
Pedro R T
PR
Romão
Laboratório de Microbiologia e Imunologia Clínica/UFPA and Programa de Pós-graduação em Ciências Farmacêuticas, Faculdade de Farmácia, Universidade Federal do Pará/UFPA, Rua Augusto Corrêa, Belém, Brasil.
Fabio R
FR
Oliveira
Laboratório de Microbiologia e Imunologia Clínica/UFPA and Programa de Pós-graduação em Ciências Farmacêuticas, Faculdade de Farmácia, Universidade Federal do Pará/UFPA, Rua Augusto Corrêa, Belém, Brasil.
Marta Chagas
MC
Monteiro
D000328:Adult; D000704:Analysis of Variance; D002374:Catalase / Q000097:blood; D002991:Clofazimine / Q000627:therapeutic use*; D065731:Cytochrome P-450 CYP2C19 / Q000378:metabolism; D003622:Dapsone / Q000097:blood / Q000378:metabolism / Q000627:therapeutic use*; D004359:Drug Therapy, Combination; D005260:Female; D005978:Glutathione / Q000097:blood; D006366:Heinz Bodies / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007917:Leprostatic Agents / Q000627:therapeutic use; D007918:Leprosy / Q000097:blood / Q000188:drug therapy*; D008297:Male; D008706:Methemoglobin / Q000378:metabolism; D008875:Middle Aged; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects*; D011485:Protein Binding; D017382:Reactive Oxygen Species / Q000097:blood; D012293:Rifampin / Q000627:therapeutic use*; D013997:Time Factors; D016896:Treatment Outcome; D055815:Young Adult
D007917:Leprostatic Agents; D017382:Reactive Oxygen Species; D003622:Dapsone; D008706:Methemoglobin; D002991:Clofazimine; D002374:Catalase; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D005978:Glutathione; D012293:Rifampin