An Experimental Model of Analgesic-Induced Renal Damage—Some Effects of ρ-Aminophenol on Rat Kidney Mitochondria

Crowe, C.A.; Calder, I. C.; Madsen, N.P.; Funder, C. C.; Green, C. R.; Ham, Kathryn N.; Tange, J. D.

doi:10.3109/00498257709035793

Cited by 36 publications

(5 citation statements)

References 17 publications

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“…PAP undergoes non-enzymatic oxidation in aqueous solutions to form numerous byproducts including benzoquinoneimine and para-aminophenoxy radical (Josephy et al 1983). These reactive intermediates may be responsible for mitochondrial damage and covalent binding observed with PAP (Crowe et al, 1977(Crowe et al, , 1979Kruidering et al, 1994). However, PAP has also been shown to cause lipid peroxidation, measured as 4-hydroxynonenal-adducted proteins (Harmon et al, 2005(Harmon et al, , 2006.…”

Section: Discussionmentioning

confidence: 99%

Contribution of reactive oxygen species to para-aminophenol toxicity in LLC-PK1 cells

Foreman¹,

Tarloff²

2008

Toxicology and Applied Pharmacology

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Para-aminophenol (PAP) causes nephrotoxicity by biochemical mechanisms that have not been fully elucidated. PAP can undergo enzymatic or non-enzymatic oxidation to form reactive intermediates. Using modulators of reactive oxygen species (ROS), the role of ROS in PAP toxicity in LLC-PK 1 cells was investigated. ROS formation was determined using a fluorescein derivative and viability using alamarBlue. Following treatment of cells with PAP, ROS formation occurred prior to loss of cell viability. Several modulators of ROS were used to identify the pathways involved in PAP toxicity. Viability was improved with catalase treatment, while viability was decreased when cells were treated with superoxide dismutase (SOD). Both catalase and SOD exert their effects outside of cells in the incubation medium, since there was no evidence of uptake of these enzymes in LLC-PK 1 cells. In cell-free incubations, hydrogen peroxide (H 2 O 2 ) was produced when 0.5 mM PAP was included in the incubation medium. Further, SOD greatly increased and catalase greatly decreased H 2 O 2 production in these cell-free incubations. These data suggest that H 2 O 2 formed in the incubation medium contributes to loss of viability following PAP treatment. When cells were coincubated with 0.5 mM PAP and tiron, pyruvate, bathocuproine, 1, 10-phenanthroline, or dimethylthiourea (DMTU), ROS formation was decreased. However, there was minimal improvement in cell viability. Paradoxically, DMTU exacerbated PAP-induced loss of viability. These data suggest ROS are generated in cells exposed to PAP but these species are not the predominant cause of cellular injury.

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Section: Discussionmentioning

confidence: 99%

Contribution of reactive oxygen species to para-aminophenol toxicity in LLC-PK1 cells

Foreman¹,

Tarloff²

2008

Toxicology and Applied Pharmacology

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“…Subcellular localisation of the covalent binding in the kidney showed that the nuclear and mitochondrial fractions had the largest percentage of bound material . Impaired mitochondrial function appears to be an early effect following PAP administration (Crowe et al 1977): the extent of covalent binding to cortical mitochondrial proteins may provide a better measure of toxicity. Calder et al (1979) and Newton et al (1983) found more extensive binding of radiolabel from 3H-PAP to renal compared to hepatic microsomal proteins.…”

Section: Discussionmentioning

confidence: 99%

Effect of ascorbic acid, acivicin and probenecid on the nephrotoxicity of 4-aminophenol in the Fischer 344 rat

1993

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4-Aminophenol (p-aminophenol, PAP) causes selective necrosis to the pars recta of the proximal tubule in Fischer 344 rats. The basis for this selective toxicity is not known but PAP can undergo oxidation in a variety of systems to form the 4-aminophenoxy free radical. Oxidation or disproportionation of this radical will form 1,4-benzoquinoneimine which can covalently bind to cellular macromolecules. We have recently reported that a glutathione conjugate of PAP, 4-amino-3-S-glutathionylphenol, is more toxic to the kidney than the parent compound itself. In this study we have examined the distribution and covalent binding of radiolabel from 4-[ring 3H]-aminophenol in the plasma, kidney and liver of rats 24 h after dosing and related these findings to the extent of nephrotoxicity. In addition, we have examined the effect of ascorbic acid which will slow the oxidation of PAP; acivicin, an inhibitor of gamma-glutamyltransferase and hence the processing of glutathione-derived conjugates; and probenecid, an inhibitor of organic anion transport on the nephrotoxicity produced by PAP. Administration of a single dose of PAP at 458 or 687 mumol kg-1 produced a dose-related alteration in renal function within 24 h which was associated with proximal tubular necrosis. The lesion at the lower dose was restricted to the S3 proximal tubules in the medullary rays, while at the higher dose it additionally affected the S3 tubules in the pars recta region of the cortex.(ABSTRACT TRUNCATED AT 250 WORDS)

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“…Indeed, Crowe et al (1977) demonstrated that, whereas oxidative phosphorylation and respiratory control were significantly reduced in mitochondria isolated from PAP-treated rats, when added directly to mitochondria from naive rats, PAP failed to alter respiratory activity, suggesting that PAP itself does not have a direct effect on mitochondria. This group further suggest that a metabolite of PAP, possibly formed in the liver, may be responsible for the mitochondrial damage.…”

Section: Effect Of Biliary Cannulation On Pap-induced Nephrotoxicitymentioning

confidence: 99%

Effects of biliary cannulation and buthionine sulphoximine pretreatment on the nephrotoxicity of para-aminophenol in the Fischer 344 rat

Gartland

Eason²,

Bonner³

et al. 1990

Arch Toxicol

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The effects of a glutathione depletor, buthionine sulphoximine (BSO) and biliary cannulation on the nephrotoxicity of p-aminophenol (PAP) have been investigated in the F344 rat. Pretreatment with BSO completely protected against the nephrotoxicity of a 50 mg/kg dose of PAP, assessed by clinical chemistry, renal histopathology, and 1H-NMR urinalysis. Biliary cannulation partially protects against nephrotoxicity induced by 100 mg/kg PAP. These data suggest that the nephrotoxicity of PAP may be due in part to the formation of a proximate toxic metabolite in the liver which is excreted in the bile, subsequently reabsorbed and transported via the systemic circulation to the kidney where the toxic effects occur.

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An Experimental Model of Analgesic-Induced Renal Damage—Some Effects of ρ-Aminophenol on Rat Kidney Mitochondria

Cited by 36 publications

References 17 publications

Contribution of reactive oxygen species to para-aminophenol toxicity in LLC-PK1 cells

Contribution of reactive oxygen species to para-aminophenol toxicity in LLC-PK1 cells

Effect of ascorbic acid, acivicin and probenecid on the nephrotoxicity of 4-aminophenol in the Fischer 344 rat

Effects of biliary cannulation and buthionine sulphoximine pretreatment on the nephrotoxicity of para-aminophenol in the Fischer 344 rat

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