Nephrotoxicity of p-aminophenol, a metabolite of acetaminophen, in the Fischer 344 rat

doi:10.1016/0041-008X(82)90017-5

Toxicology and Applied Pharmacology

Volume 65, Issue 2, 15 September 1982, Pages 336-344

https://doi.org/10.1016/0041-008X(82)90017-5 Get rights and content

Abstract

Acetaminophen (APAP) produces proximal tubular necrosis in the Fischer 344 rat. APAP is deacetylated to p-aminophenol (PAP) in the hamster, and PAP has been reported to be a potent specific cortical nephrotoxicant in the rat. However, the role of PAP in APAP nephrotoxicity has not been defined. Therefore, it was of interest to quantify PAP formation after APAP administration and to correlate PAP formation with renal injury produced by APAP in the Fischer 344 rat. Urinary PAP excretion, measured as an index of PAP formation, increased with increasing doses of APAP. In addition, APAP was metabolized to PAP in isolated perfused kidneys. PAP at doses as low as 100 mg/kg produced significant renal toxicity (elevation in blood urea nitrogen and reduction in accumulation of p-aminohippurate by thin renal cortical slices). Ortho- and meta-aminophenol were not nephrotoxic. Pretreatment with polybrominated biphenyls or β-naphthoflavone, inducers of mixed function oxidases, protected against nephrotoxicity of PAP, possibly as a result of enhanced hepatic biotransformation of the parent compound. These studies indicate that PAP is a potent, selective nephrotoxicant that can be generated from APAP by the kidney and may be responsible for the renal necrosis subsequent to APAP administration.

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In a long-term feeding study, aniline or structurally related compounds (PCA, o-TOL) produced spleen tumors in rats given high doses in 2-year bioassay studies.24 PAP is a nephrotoxicant in the rat, which has been shown to produce selective necrosis to renal proximal tubules.25 The model compounds were reported to be mainly eliminated via liver metabolism, rapidly absorbed from the small intestine, and passively permeated through tissue and cellular membranes with no known transporter.26–29
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Commercial oxidative hair dye often contains PAP because it is one of the primary intermediate in hair dye formation process [5,6]. The nephrotoxicity of PAP has been the subject of several studies [7–10]. Several methods have been used for analysis of PAP, including electron capture gas chromatography [11], high-performance liquid chromatography with amperometric detection [12], flow injection analysis with spectrophotometric detection [3], colorimetric methods [13] and capillary zone electrophoresis [14].
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Also, AA shows toxicity to hepatocyte on account of the generation of N-acetyl-p-benzoquinonimine by cytochrome P450 and covalent binding to some proteins [12], but AA had no effects on the aquatic organisms. PA is 5 to 10 times more potent than AA as a nephrotoxicant in F344 rats [24], and the inhibition of AA deacetylation by preventing the formation of PA greatly reduced renal toxicity suggesting that renal toxicity of AA is due to PA at least in part [25]. From these reports, it is tempting to speculate that compound 1 has a same mechanism on account of the similarity of chemical structure to PA.
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Pyruvate has been observed to reduce the nephrotoxicity of some agents by maintaining glutathione status and preventing lipid peroxidation. This study examined the mechanism for pyruvate protection of p-aminophenol (PAP) nephrotoxicity. Renal cortical slices from male Fischer 344 rats were incubated for 30–120 min with 0, 0.1, 0.25 or 0.5 mM PAP in oxygenated Krebs buffer containing 0 or 10 mM pyruvate or glucose (1.28 or 5.5 mM). LDH leakage was increased above control by 0.25 and 0.5 mM PAP beginning at 60 min and by 0.1 mM PAP at 120 min. Pyruvate prevented an increase in LDH leakage at 60- and 120-min exposure to 0.1 and 0.25 mM PAP. Pyruvate also prevented a decline in ATP levels. Glucose (1.28 and 5.5 mM) provided less protection than pyruvate from PAP toxicity. Total glutathione levels were diminished by 0.1 and 0.25 mM PAP within 60 and 30 min, respectively. Pyruvate prevented the decline in glutathione by 0.1 mM PAP at both time periods and at 30 min for 0.25 mM PAP. Pyruvate reduced the magnitude of glutathione depletion by 0.25 mM PAP following a 60-min incubation. Glutathione disulfide (GSSG) levels in renal slices were increased at 60 min by exposure to 0.25 mM PAP, while pyruvate prevented increased GSSG levels by PAP. Pyruvate also reduced the extent of 4-hydroxynonenal (4-HNE)-adducted proteins present after a 90-min incubation with PAP. These results indicate that pyruvate provided protection for PAP toxicity by providing an energy substrate and reducing oxidative stress.

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^☆: Portions of this study have been presented previously (Pharmacologist (1981), 23, 190).

²: Supported by a Monsanto Predoctoral Fellowship in Toxicology.

³: Present address: Sterling-Winthrop Research Institute, Rensselaer, N.Y. 12144.

View full text

Nephrotoxicity of p-aminophenol, a metabolite of acetaminophen, in the Fischer 344 rat☆

Abstract

Chem.-Biol. Interact.

Chem.-Biol. Interact.

Toxicol. Appl. Pharmacol.

Lancet

Kidney Int.

Acetaminophen-induced hepatic necrosis and renal failure

J. Amer. Med. Assoc.

Comparative nephrotoxicity of aspirin and phenacetin derivatives

Brit. Med. J.

Nephrotoxicity and molecular structure

Xenobiotica

Acetaminophen nephrotoxicity: Studies on renal acetylation and deacetylation

J. Pharmacol. Exp. Ther.

Paracetamol-induced acute renal failure in the absence of fulminant liver damage

Brit. Med. J.

Renal tubular transport: Accumulation of p-aminohippurate by rabbit kidney slices

Amer. J. Physiol.