Direct and metabolism‐dependent toxicity of sulphasalazine and its principal metabolites towards human erythrocytes and leucocytes.

Pirmohamed, Munir; Coleman,; Hussain, Fazal; Breckenridge, AM; Park, BK

doi:10.1111/j.1365-2125.1991.tb03903.x

Cited by 56 publications

(12 citation statements)

References 33 publications

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“…Neutrophil and lymphocyte membrane integrity was assessed by trypan blue dye exclusion as described previously ( Pirmohamed et al ., 1991 ). Cells were incubated with SMX, SMX‐NHOH or SMX‐NO (1–1000 μ M ) in Dulbecco's PBS (1 ml, pH 7.4) in a shaking water bath at 37°C for 1 h. Data represents the percentage of trypan blue stained cells/total number of cells.…”

Section: Methodsmentioning

confidence: 99%

Cellular disposition of sulphamethoxazole and its metabolites: implications for hypersensitivity

Naisbitt

Hough

Gill

et al. 1999

British J Pharmacology

127

114

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1 Bioactivation of sulphamethoxazole (SMX) to chemically-reactive metabolites and subsequent protein conjugation is thought to be involved in SMX hypersensitivity. We have therefore examined the cellular metabolism, disposition and conjugation of SMX and its metabolites in vitro. 2 Flow cytometry revealed binding of N-hydroxy (SMX-NHOH) and nitroso (SMX-NO) metabolites of SMX, but not of SMX itself, to the surface of viable white blood cells. Cellular haptenation by SMX-NO was reduced by exogenous glutathione (GSH). 3 SMX-NHOH and SMX-NO were rapidly reduced back to the parent compound by cysteine (CYS), GSH, human peripheral blood cells and plasma, suggesting that this is an important and ubiquitous bioinactivation mechanism. 4 Fluorescence HPLC showed that SMX-NHOH and SMX-NO depleted CYS and GSH in bu er, and to a lesser extent, in cells and plasma. 5 Neutrophil apoptosis and inhibition of neutrophil function were induced at lower concentrations of SMX-NHOH and SMX-NO than those inducing loss of membrane viability, with SMX having no e ect. Lymphocytes were signi®cantly (P50.05) more sensitive to the direct cytotoxic e ects of SMX-NO than neutrophils. 6 Partitioning of SMX-NHOH into red blood cells was signi®cantly (P50.05) lower than with the hydroxylamine of dapsone. 7 Our results suggest that the balance between oxidation of SMX to its toxic metabolites and their reduction is an important protective cellular mechanism. If an imbalance exists, haptenation of the toxic metabolites to bodily proteins including the surface of viable cells can occur, and may result in drug hypersensitivity.

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Section: Methodsmentioning

confidence: 99%

Cellular disposition of sulphamethoxazole and its metabolites: implications for hypersensitivity

Naisbitt

Hough

Gill

et al. 1999

British J Pharmacology

127

114

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“…However, when normal subjects were supplemented with ascorbate, leukocyte ascorbate levels increased, and both direct and delayed cytotoxicity decreased significantly. Others have shown that exogenous ascorbate decreases sulfonamide cytotoxicity in vitro (Pirmohamed et al, 1991). Our results suggest that pharmacologically achievable concentrations of ascorbate are likely to decrease the cytotoxicity of even high concentrations of SMX-NO in vivo.…”

Section: Discussionmentioning

confidence: 46%

Roles of endogenous ascorbate and glutathione in the cellular reduction and cytotoxicity of sulfamethoxazole-nitroso

et al. 2006

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“…Nitric oxide (14), bacterial toxins (15) and many drugs (16) can induce methemoglobin formation. Normally the haemoglobin molecule and the membrane of the erythrocyte are protected by the reducing systems within the erythrocyte.…”

Section: Discussionmentioning

confidence: 99%

Association Between Oxidative Damage Markers and Self-Reported Temporomandibular Dysfunction Symptoms in Patients with Chronic Fatigue Syndrome

Richards

McGregor

Roberts

2004

Journal of Chronic Fatigue Syndrome

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Full blood counts, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), haematinics and markers for oxidative stress were measured on thirty-three patients diagnosed with chronic fatigue Ross S. Richards is Faculty syndrome (CFS) and twenty-seven age and sex matched controls. The CFS patients had increased prevalence of symptoms of temporomandibular dysfunction (TMD). Jaw muscle pain was associated with increases in methaemoglobin (P < .002), ferritin (P < .02) and malondialdehyde (P < .007) whilst temporomandibular joint (TMJ) clicking and/or locking was associated with increases in methaemoglobin (P < .001), malondialdehyde (P < .05) and vitamin B 12 (P < .02) levels. Multiple regression analysis found methaemoglobin to be the principle component associated with TMD symptoms in the CFS patients. Increases in scalar severity responses to jaw muscle pain and TMJ clicking and/or locking were positively correlated with methaemoglobin by multiple regression. These data indicate that oxidative stress due to excess free radical formation was associated with jaw muscle pain in CFS patients and suggest that these symptoms were likely to be associated with a pathogen-associated aetiology.

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Direct and metabolism‐dependent toxicity of sulphasalazine and its principal metabolites towards human erythrocytes and leucocytes.

Cited by 56 publications

References 33 publications

Cellular disposition of sulphamethoxazole and its metabolites: implications for hypersensitivity

Cellular disposition of sulphamethoxazole and its metabolites: implications for hypersensitivity

Roles of endogenous ascorbate and glutathione in the cellular reduction and cytotoxicity of sulfamethoxazole-nitroso

Association Between Oxidative Damage Markers and Self-Reported Temporomandibular Dysfunction Symptoms in Patients with Chronic Fatigue Syndrome

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