In Vitro Protective Effect and Antioxidant Mechanism of Resveratrol Induced by Dapsone Hydroxylamine in Human Cells.

Rosyana V Albuquerque,Sebastião Aldo S Valente,Vera C Valente,Lílian L Amado,Michael D Coleman,Marta Chagas Monteiro,Nívea S Malcher,Rosivaldo Sa Borges,Danielle C Dos Santos,Aditya Bhushan Pant

doi:10.1371/journal.pone.0134768

Rosyana V Albuquerque, Sebastião Aldo S Valente + Show 8 more

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https://doi.org/10.1371/journal.pone.0134768

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Abstract

Dapsone (DDS) hydroxylamine metabolites cause oxidative stress- linked adverse effects in patients, such as methemoglobin formation and DNA damage. This study evaluated the ameliorating effect of the antioxidant resveratrol (RSV) on DDS hydroxylamine (DDS-NHOH) mediated toxicity in vitro using human erythrocytes and lymphocytes. The antioxidant mechanism was also studied using in-silico methods. In addition, RSV provided intracellular protection by inhibiting DNA damage in human lymphocytes induced by DDS-NHOH. However, whilst pretreatment with RSV (10–1000 μM significantly attenuated DDS-NHOH-induced methemoglobinemia, but it was not only significantly less effective than methylene blue (MET), but also post-treatment with RSV did not reverse methemoglobin formation, contrarily to that observed with MET. DDS-NHOH inhibited catalase (CAT) activity and reactive oxygen species (ROS) generation, but did not alter superoxide dismutase (SOD) activity in erythrocytes. Pretreatment with RSV did not alter these antioxidant enzymes activities in erythrocytes treated with DDS-NHOH. Theoretical calculations using density functional theory methods showed that DDS-NHOH has a pro-oxidant effect, whereas RSV and MET have antioxidant effect on ROS. The effect on methemoglobinemia reversion for MET was significantly higher than that of RSV. These data suggest that the pretreatment with resveratrol may decrease heme-iron oxidation and DNA damage through reduction of ROS generated in cells during DDS therapy.

Highlights

Leprosy, known as Hansen’s disease, is a chronic infectious disease caused by the acid-fast bacillus Mycobacterium leprae
The current strategy for leprosy control recommended by the World Health Organization (WHO) is based on multidrug therapy (MDT) that consists of the combination of rifampicin, clofazimine and dapsone (4,4'-diaminodiphenylsulfone, DDS) for multi-bacillary leprosy patients and rifampicin and DDS for pauci-bacillary leprosy patients [3]
To evaluate the effect of RSV in methemoglobin formation induced by DDS-NHOH (2.5; 5.0 and 7.5 μg/ml), erythrocytes were pretreated with different concentrations of RSV (10; 100; 200 and 1000 μM) for 60 min and, after these cells were incubated with DDS-NHOH (2.5; 5.0 and 7.5 μg/ml)

Summary

Introduction

Known as Hansen’s disease, is a chronic infectious disease caused by the acid-fast bacillus Mycobacterium leprae. Leprosy remains a significant public health problem in 105 countries, as reported by the World Health Organization (WHO). In 2012, 33,955 new cases were detected in Brazil alone [3] and epidemiological studies have reported that a high prevalence of leprosy remains in some regions of Brazil [4,5]. DDS therapy is responsible for hematological adverse reactions, such as methemoglobinemia and anemia [6,7]. These effects are associated with the hydroxylamine metabolite of DDS (DDS-NHOH) that is formed through N-hydroxylation by hepatic cytochromes P450, CYP2C9 and CYP2C19 [6,8]. Some studies have reported cytogenetic damage and genotoxicity in leprosy patients under treatment with anti-leprotic drugs [10,11]

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