Kidney Lesions Induced in Rats by P-aminophenol

Green, C. R.; Ham, Kathryn N.; Tange, J. D.

doi:10.1136/bmj.1.5637.162

Cited by 82 publications

(30 citation statements)

References 5 publications

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“…This observed toxicity is entirely in agreement with our 28-day study results, although the actual daily intake in the diet study was not given. A structural isomer, 4-aminophenol is a major metabolite of the analgesic and antipyretic drug, acetaminophen, and is known to exert renal toxicity (Green et al, 1969;Calder et al, 1979). Mechanistic studies in rats suggest that 4-aminophenol may be oxidized to benzoquinoneimine and then conjugated with glutathione in the liver to be excreted in the bile, and subsequently reabsorbed and transported via the systemic circulation to the kidney, where toxic effects occur (Garland et al, 1990).…”

Section: Discussionmentioning

confidence: 99%

Comparative Toxicity Study of 3-Aminophenol in Newborn and Young Rats

et al. 2002

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-Repeated dose toxicity of 3-aminophenol was examined on oral administration to newborn and young rats, and susceptibility was analyzed in terms of the no observed adverse effect level (NOAEL) and the unequivocally toxic level. In the 18-day newborn rat study, starting at day 4 after birth, tremors and depression of body weight gain were observed, as well as hypertrophy of thyroid follicular epithelial cells and increases of relative liver and kidney weights at 240 mg/kg. Increase of relative liver weights in males and decrease of blood sugar in females without any histopathological changes at 80 mg/ kg were not considered to be adverse effects. No chemical-related changes were observed at 24 mg/kg. Abnormalities of external development and reflex ontogeny in the newborn were not observed. In the 28-day study, starting at 5 weeks of age, depression of body weight gain, tremors, anemia, and liver, kidney and thyroid toxicity were observed at 720 mg/kg. Although slight pigmentation in the renal proximal tubular epithelium was observed in females at 240 mg/kg, this was not considered to be an adverse effect because of the lack of changes in related toxicological parameters. It was concluded that the NOAEL is 80 mg/kg/day in newborn rats and 240 mg/kg/day in young rats, with unequivocally toxic levels of 240 mg/kg/day and 720 mg/kg/day, respectively. Based on these two endpoints, the susceptibility of newborn rats to the chemical was approx. 3 times higher than that of young rats, consistent with our previous results for 4-nitrophenol and 2,4-dinitrophenol.

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Section: Discussionmentioning

confidence: 99%

Comparative Toxicity Study of 3-Aminophenol in Newborn and Young Rats

et al. 2002

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“…35, No. 4, 2007 MARKERS OF ANALGESIC NEPHROTOXICITY 529 DISCUSSION To study the modulation of protein expression at the tissue level and in biofluids, we have chosen to evaluate a model of analgesic nephropathy utilizing PAP, a toxicant known to cause necrosis of the renal PST (Green et al, 1969;Davis et al, 1983;Fowler et al, 1994;Harmon et al, 2005). This work followed the dose-and time-dependent progression of ATN lesions and protein expression changes that correlated with morphological stages of injury.…”

Section: Cleaved Caspasementioning

confidence: 99%

“…This selectivity might be related to the differential perfusion of the tubular areas (Fowler et al, 1991). The PAP-induced tubular damage appears early after administration (Green et al, 1969;Davis et al, 1983), allowing the use of early time points to study the progress of the lesions and the changes in the expression of relevant proteins.…”

Section: Introductionmentioning

confidence: 99%

“…It induces acute tubular necrosis (ATN) affecting the proximal straight tubule (PST; S3 segment of the proximal tubule), a property that justifies the use of PAP as a model for acute analgesic nephropathy (Green et al, 1969). The lesions produced by PAP in the kidney are dose-responsive: at low dose they affect only the PST within the medullary rays (MRs), with a selectivity for cortical nephrons, while at higher concentrations they extend to the PSTs in the outer stripe of outer medulla (OSOM; Fowler et al, 1991Fowler et al, , 1994.…”

Section: Introductionmentioning

confidence: 99%

“…Para-aminophenol (PAP; also known as 4-aminophenol or p-aminophenol) is a well-known metabolite of acetaminophen and phenacetin, and a derivative of anilines in industrial use (Green et al, 1969;Newton et al, 1983;McCarthy et al, 1985;Kanbak et al, 1996). It induces acute tubular necrosis (ATN) affecting the proximal straight tubule (PST; S3 segment of the proximal tubule), a property that justifies the use of PAP as a model for acute analgesic nephropathy (Green et al, 1969).…”

Section: Introductionmentioning

confidence: 99%

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Clinicopathological and Tissue Indicators of Para-Aminophenol Nephrotoxicity in Sprague–Dawley Rats

Yang¹,

Trajkovic

Illanes³

et al. 2007

Toxicol Pathol

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A model of para-aminophenol (PAP) nephrotoxicity in Sprague-Dawley rats was utilized to characterize potential indicators of toxicity in the kidney and in biofluids, and to chronicle the progression of acute renal injury. Rats were administered PAP at a low or high dose and examined terminally at 6, 24 and 48 hours (4 animals/group with matching controls). Acute tubular necrosis was observed in the medullary rays (low and high doses) and the outer stripe of outer medulla (high dose only) as early as 6 hours postdosing. Starting at 24 hours, regeneration of the tubular epithelium was evident in both low and high dose studies. Associated with the tubular lesions, we observed elevation of urinary α-glutathione S-transferase levels, an indicator of proximal tubular injury. By immunohistochemistry of the kidney, decreased γ -glutamylcysteine synthetase expression correlated with tubular injury, especially at high dose, whereas elevation of vimentin, osteopontin, and Ki-67 expression was concurrent with tubular regeneration. Clusterin and kidney injury molecule-1 displayed expression patterns characteristic of both renal injury and regeneration. Taken together, this study provided insight into the progression of nephrotoxicity, and allowed the evaluation of potential urinary and tissue protein biomarkers that could complement the early detection of acute tubular injury.

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Haemolytic activity and nephrotoxicity of 2‐hydroxy‐1,4‐naphthoquinone in rats

Munday

Smith

Fowke

1991

J of Applied Toxicology

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The short-term toxicity of 2-hydroxy-1,4-naphthoquinone (lawsone) and 2-methyl-1,4-naphthoquinone (menadione) has been compared in rats. 2-Methyl-1,4-naphthoquinone has been shown previously to cause haemolytic anaemia in animals, and this was confirmed in the present experiment. 2-Hydroxyl-1,4-naphthoquinone was found also to cause haemolysis, in a dose-dependent manner, as reflected by decreased blood packed cell volumes and haemoglobin levels and by histopathological changes in spleen, liver and kidney. With both naphthoquinones, the haemolysis was of the oxidative type, characterized by the presence of Heinz bodies within erythrocytes. Haemolysis was the only toxic change identified in rats dosed with 2-methyl-1,4-naphthoquinone. In contrast, 2-hydroxyl-1,4-naphthoquinone was not only a haemolytic agent but also a nephrotoxin, causing renal enlargement, elevated plasma levels of urea and creatinine and histologically-identified tubular necrosis, largely confined to the distal segment of the proximal convoluted tubules. The relationship between the in vivo toxic effects of these naphthoquinones and previously-reported data on their in vitro cytotoxic action is discussed.

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Kidney Lesions Induced in Rats by P-aminophenol

Cited by 82 publications

References 5 publications

Comparative Toxicity Study of 3-Aminophenol in Newborn and Young Rats

Comparative Toxicity Study of 3-Aminophenol in Newborn and Young Rats

Clinicopathological and Tissue Indicators of Para-Aminophenol Nephrotoxicity in Sprague–Dawley Rats

Haemolytic activity and nephrotoxicity of 2‐hydroxy‐1,4‐naphthoquinone in rats

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