Formation of Free Radicals and Protein Mixed Disulfides in Rat Red Cells Exposed to Dapsone Hydroxylamine

Bradshaw, Timothy P.; McMillan, David C.; Crouch, Rosalie K.; Jollow, David J.

doi:10.1016/s0891-5849(96)00542-4

Cited by 29 publications

(15 citation statements)

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“…7A). The fact that ferrylhemoglobin was detected only by conversion to sulfhemoglobin suggests a steady low-level production of this oxidant species during the incubation period (Bradshaw et al, 1997). Production of ferryl heme was dependent on MAQ-NOH concentration (Fig.…”

Section: Downloaded Frommentioning

confidence: 91%

“…Formation of methemoglobin and ferrylhemoglobin in MAQ-NOHtreated red cell suspensions was determined as described previously (Harrison and Jollow, 1987;Bradshaw et al, 1997). The amount of ferrylhemoglobin was measured in red cell incubates pretreated with sodium sulfide (2 mM), which irreversibly converts the unstable ferryl heme species to sulfhemoglobin (Giulivi and Davies, 1990).…”

Section: Methodsmentioning

confidence: 99%

“…Although a hydroxyl radical has previously been shown to be generated in red cells exposed to other hemolytic N-hydroxylamines, such dapsone hydroxylamine (Bradshaw et al, 1997), the mechanism by which the radical is generated is unclear. It is well known that oxyhemoglobin exists in the red cell as an equilibrium mixture that includes a superoxideferriheme component.…”

Section: Maq-noh Effects On Rat Erythrocytes 1125mentioning

confidence: 99%

“…This interaction has been shown to produce greater than stoichiometric amounts of reactive oxygen species (i.e., hydrogen peroxide, superoxide anion radical, and hydroxyl radical) and sulfur-centered free radicals (i.e., glutathione and hemoglobin thiyl radicals) and, thus, has been proposed to generate reactive species capable of causing cellular injury (Rostorfer and Cormier, 1957;Maples et al, 1990;Bradshaw et al, 1995;Bradshaw et al, 1997).…”

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Primaquine-Induced Hemolytic Anemia: Formation of Free Radicals in Rat Erythrocytes Exposed to 6-Methoxy-8-hydroxylaminoquinoline

Bolchoz

Gelasco

Jollow³

et al. 2002

The Journal of Pharmacology and Experimental Therapeutics

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Primaquine is an important antimalarial drug that is often doselimited in therapy by the onset of hemolytic anemia. We have shown recently that an N-hydroxy metabolite of primaquine, 6-methoxy-8-hydroxylaminoquinoline (MAQ-NOH), is a directacting hemolytic agent in rat red cells and that the hemolytic activity of this metabolite is associated with GSH oxidation and oxidative damage to both membrane lipids and skeletal proteins. To determine whether the formation of free radicals may be involved in this process, rat red cells (40% suspensions) were incubated with hemolytic concentrations of MAQ-NOH (150 -750 M) and examined by EPR spectroscopy using 2-ethoxycarbonyl-2-methyl-3,4-dihydro-2H-pyrrole-1-oxide (EMPO) as a spin trap. Addition of MAQ-NOH to red cell suspensions containing 10 mM EMPO gave rise to an EPR spectrum with hyperfine constants consistent with those of an EMPO-hydroxyl radical adduct standard. Of interest, formation of EMPO-OH was constant for up to 20 min and dependent on the presence of erythrocytic GSH. Although no other radical adduct signals were detected in the cells by EPR, spectrophotometric analysis revealed the presence of ferrylhemoglobin, which indicates that hydrogen peroxide is generated under these experimental conditions. The data support the hypothesis that oxygen-derived and possibly other free radicals are involved in the mechanism underlying MAQ-NOH-induced hemolytic anemia.Hemolytic anemia and methemoglobinemia are well recognized dose-limiting side effects in the therapeutic use of arylamine drugs, such as primaquine and dapsone (Beutler, 1969). Because these compounds are not hemotoxic when incubated with red cells in vitro, it has long been appreciated that metabolites are responsible for the onset of the hemolytic response. In the cases of aniline (Harrison and Jollow, 1986), dapsone (Grossman and Jollow, 1988), and phenacetin (Jensen and Jollow, 1991), we have shown that the hemolytic metabolites are their N-hydroxy derivatives. Primaquine metabolism, on the other hand, is relatively more complex, and the metabolites that mediate the hemotoxic responses have not been identified. A variety of known and putative phenolic metabolites of primaquine are redox-active and therefore have the potential to mediate primaquine hemotoxicity (Strother et al., 1984;Baird et al., 1986;Fletcher et al., 1988;Agarwal et al., 1991); however, direct evidence for their hemolytic activity is lacking. We have recently explored an alternative hypothesis-that primaquine hemotoxicity is mediated by an N-hydroxylated metabolite, 6-methoxy-8-hydroxylaminoquinoline (MAQ-NOH).Although the mechanism underlying the damage and removal of red cells by hemolytic N-hydroxylamines remains unclear, oxidative stress has long been considered to play a prominent role in the process (for review, see Beutler, 1971). This concept is based on the well known association of hemotoxicity with oxidation of erythrocytic GSH (to glutathione disulfide and glutathione protein-mixed disulfides), with methemoglobin f...

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Section: Downloaded Frommentioning

confidence: 91%

Section: Methodsmentioning

confidence: 99%

Section: Maq-noh Effects On Rat Erythrocytes 1125mentioning

confidence: 99%

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Primaquine-Induced Hemolytic Anemia: Formation of Free Radicals in Rat Erythrocytes Exposed to 6-Methoxy-8-hydroxylaminoquinoline

Bolchoz

Gelasco

Jollow³

et al. 2002

The Journal of Pharmacology and Experimental Therapeutics

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“…Despite its long-term use, the issue of whether its mode of action as an antioxidant or pro-oxidant is a still ongoing debate (Niwa et al, 1984;Anderson et al, 1987;Bradshaw et al, 1997;Reilly et al, 1999). Recently, we observed and reported an interesting phenomenon that the lifespan of Hansen disease patients in Korea, most of whom have taken DDS for several decades, would be longer than that of the ordinary people despite their socioeconomic and medical disadvantages (summarized in Shimokawa et al 2009).…”

Section: Introductionmentioning

confidence: 99%

Protective effect of 4,4'-diaminodiphenylsulfone against paraquat-induced mouse lung injury

et al. 2011

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Although 4,4'-diaminodiphenylsulfone (DDS, dapsone) has been used to treat several dermatologic conditions, including Hansen disease, for the past several decades, its mode of action has remained a topic of debate. We recently reported that DDS treatment significantly extends the lifespan of the nematode C. elegans by decreasing the generation of reactive oxygen species. Additionally, in in vitro experiments using non-phagocytic human fibroblasts, we found that DDS effectively counteracted the toxicity of paraquat (PQ). In the present study, we extended our work to test the protective effect of DDS against PQ in vivo using a mouse lung injury model. Oral administration of DDS to mice significantly attenuated the lung tissue damage caused by subsequent administration of PQ.Moreover, DDS reduced the local expression of mRNA transcripts encoding inflammation-related molecules, including endothelin-1 (ET-1), macrophage inflammatory protein-1α (MIP-1α), and transforming growth factor-β (TGF-β). In addition, DDS decreased the PQ-induced expression of NADPH oxidase mRNA and activation of protein kinase Cμ (PKCμ). DDS treatment also decreased the PQ-induced generation of superoxide anions in mouse lung fibroblasts. Taken together, these data suggest the novel efficacy of DDS as an effective protective agent against oxidative stress-induced tissue damages.

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Free Radical Metabolites in Arylamine Toxicity

Siraki

2013

Advances in Molecular Toxicology

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Formation of Free Radicals and Protein Mixed Disulfides in Rat Red Cells Exposed to Dapsone Hydroxylamine

Cited by 29 publications

References 38 publications

Primaquine-Induced Hemolytic Anemia: Formation of Free Radicals in Rat Erythrocytes Exposed to 6-Methoxy-8-hydroxylaminoquinoline

Primaquine-Induced Hemolytic Anemia: Formation of Free Radicals in Rat Erythrocytes Exposed to 6-Methoxy-8-hydroxylaminoquinoline

Protective effect of 4,4'-diaminodiphenylsulfone against paraquat-induced mouse lung injury

Free Radical Metabolites in Arylamine Toxicity

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