Dapsone induces oxidative stress and impairs antioxidant defenses in rat liver

Veggi, Luis M.; Pretto, Luciana Meggiolaro; Ochoa, Elena J.; Catania, Viviana A.; Luquita, Marcelo G.; Taborda, Diego R.; Pozzi, Enrique J. Sánchez; Ikushiro, Shinichi; Coleman, Michael D.; Roma, Marcelo G.; Mottino, Aldo D.

doi:10.1016/j.lfs.2008.05.016

Cited by 21 publications

(14 citation statements)

References 49 publications

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“…Most studies on the pro-oxidant effects of DDS have been based on its use at high concentrations. For example, in human dermal fibroblasts, a high dose of DDS (1.5 mM) induced oxidative stress and glutathione depletion (10), but in rat livers, DDS administration at a dose of 30 mg/kg body weight resulted in oxidative stress (11). Therefore, the debate regarding the nature of DDS as a pro-oxidant or antioxidant appears to reflect the dosage effect.…”

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confidence: 99%

DDS, 4,4′-diaminodiphenylsulfone, extends organismic lifespan

Cho

Park

Keam

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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DDS, 4,4′-diaminodiphenylsulfone, is the most common drug prescribed to treat Hansen disease patients. In addition to its antibacterial activity, DDS has been reported to be involved in other cellular processes that occur in eukaryotic cells. Because DDS treatment significantly enhances the antioxidant activity in humans, we examined its effect on lifespan extension. Here we show that DDS extends organismic lifespan using Caenorhabditis elegans as a model system. DDS treatment caused a delay in aging and decreased the levels of a mitochondrial complex. The oxygen consumption rate was also significantly lowered. Consistent with these data, paraquat treatment evoked less reactive oxygen species in DDS-treated worms, and these worms were less sensitive to paraquat. Interestingly enough, all of the molecular events caused by DDS treatment were consistently reproduced in mice treated with DDS for 3 mo and in the C2C12 muscle cell line. Structural prediction identified pyruvate kinase (PK) as a protein target of DDS. Indeed, DDS bound and inhibited PK in vitro and inhibited it in vivo, and a PK mutation conferred extended lifespan of C. elegans. Supplement of pyruvate to the media protected C2C12 cells from apoptosis caused by paraquat. Our findings establish the significance of DDS in lowering reactive oxygen species generation and extending the lifespan, which renders the rationale to examining the possible effect of DDS on human lifespan extension.F irst synthesized a century ago, 4,4′-diaminodiphenylsulfone (DDS) is a drug still used to treat many skin diseases. Specifically, DDS is a principal drug in a multidrug regimen recommended by the World Health Organization for the treatment of leprosy (1-4). DDS acts as an antibiotic in a manner similar to sulphonamides by inhibiting bacterial synthesis of dihydrofolic acid through competition with para-aminobenzoic acid (PABA) for the active site of dihydropteroate synthetase (DHPS) (5). In addition to its antibacterial activity, DDS has been reported to be involved in other cellular processes that occur in eukaryotic cells, such as inflammation, migration, and apoptosis (6). However, there has been controversy over the issue of whether DDS acts as a pro-oxidant (especially when a higher dose of DDS is used rather than a standard dose) or antioxidant (7-9). Most studies on the pro-oxidant effects of DDS have been based on its use at high concentrations. For example, in human dermal fibroblasts, a high dose of DDS (1.5 mM) induced oxidative stress and glutathione depletion (10), but in rat livers, DDS administration at a dose of 30 mg/kg body weight resulted in oxidative stress (11). Therefore, the debate regarding the nature of DDS as a pro-oxidant or antioxidant appears to reflect the dosage effect. Another interesting observation is that Hansen disease patients in Korea, who usually have taken DDS for several decades, had a longer lifespan in spite of their socioeconomical disadvantages (12). This finding prompted us to examine whether and how DDS treatment extends an...

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mentioning

confidence: 99%

DDS, 4,4′-diaminodiphenylsulfone, extends organismic lifespan

Cho

Park

Keam

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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“…Reduced glutathione (GSH), the most important endogenous antioxidant, directly scavenges reactive oxygen species 14 . Glutathione-S-transferases (GSTs) are detoxification enzymes that catalyze the conjugation of GSH to chemical toxicants and environmental pollutants and to peroxides formed during oxidative stress 15 .…”

Section: Resultsmentioning

confidence: 99%

Proteomic analysis of rat liver proteins differentially induced by trichloroethylene

Park¹,

Nam²,

Ryu

et al. 2010

BioChip J

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Trichloroethylene (TCE), a volatile and lipophilic solvent widely used in industrial degreasing applications, is believed to be toxic in humans. To identify possible protein biomarkers of early TCE-induced hepatotoxicity, we treated rats with a single dose of TCE equivalent to 10% of LD 50 and analyzed their liver proteomes 72 h after dosing. We identified eight liver proteins that exhibited a TCE-induced change in expression level of at least 2-fold; three of these proteins were upregulated and the rest were downregulated. Because these proteins changed significantly in abundance in the absence of notable hepatotoxicity in vivo, they may be useful as one of the candidates of early predictive biomarkers of TCE exposure in rats.

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“…The process of methemoglobin formation depletes reduced glutathione, then generates reactive oxygen species and impairs antioxidant defenses. 23 In one study in non-insulin-dependent diabetic patients, HbA1c levels were significantly negatively correlated with scavenging capacity of oxygen radicals. 24 HbA1c production is also decreased under oxygen tension.…”

Section: Discussionmentioning

confidence: 98%

Falsely decreased HbA1c in a type 2 diabetic patient treated with dapsone

Lai

Wang

et al. 2012

Journal of the Formosan Medical Association

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Glycated hemoglobin A1c (HbA1c) is an important indicator of glycemic control. The current recommendation for glycemic control based on HbA1c values has been widely accepted. However, HbA1c values depend on the lifespan of erythrocytes and the assay methods used. Here, we report the case of a patient with type 2 diabetes with unusual falling of HbA1c due to interference from dapsone treatment for leukocytoclastic vasculitis. He was a 52-year-old man, who was diagnosed with type 2 diabetes mellitus 5 years previously and who had been treated in our hospital in the past 3 years. Glycemia was controlled by sulfonylurea and metformin. During the 3-years follow-up period, HbA1c dropped significantly during the addition of dapsone treatment, although plasma glucose levels remained stable. HbA1c levels were raised after discontinuation of dapsone. With rechallenge of dapsone usage, HbA1c decreased again. We conclude that dapsone may be the cause of artificially low HbA1c. Other measurements to monitor glycemic control should be considered when dapsone is used for the treatment of concurrent disorders, such as autoimmune disease and pneumocystis jiroveci pneumonia.

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Dapsone induces oxidative stress and impairs antioxidant defenses in rat liver

Cited by 21 publications

References 49 publications

DDS, 4,4′-diaminodiphenylsulfone, extends organismic lifespan

DDS, 4,4′-diaminodiphenylsulfone, extends organismic lifespan

Proteomic analysis of rat liver proteins differentially induced by trichloroethylene

Falsely decreased HbA1c in a type 2 diabetic patient treated with dapsone

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