Abstract
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-[ring3H]-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 γ-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 μmol 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. Administration of ascorbic acid protected rats against the nephrotoxicity produced by PAP, markedly reducing the effect on renal function, and the extent of renal tubular necrosis. Associated with this protection was a reduction in the concentration of both total and covalently bound radiolabel from PAP in the kidney. In contrast, prior treatment with acivicin slightly potentiated the nephrotoxicity of PAP at the lower dose of 458 μmol kg−1, by increasing the extent of proximal tubular necrosis and azotemia. In association with this potentiation the concentration of both total and covalently bound radiolabel from PAP in the kidney was increased. Prior treatment with probenecid had little or no effect on the nephrotoxicity of PAP or on the distribution of radiolabel from PAP in the kidney. These studies indicate that oxidation of PAP to form a metabolite which can covalently bind to renal proteins may be an important step in the nephrotoxic process and that treatment with ascorbic acid reduces this and thereby affords protection.
Similar content being viewed by others
References
Anon (1988) Final Report on the safety assessment ofp-aminophenol,m-aminophenol ando-aminophenol. J Am Coll Toxicol 7: 279–333
Calder IC, Funder CC, Green CR, Ham KN, Tange JD (1971) Comparative nephrotoxicity of aspirin and phenacetin derivatives. BMJ 4: 518–521
Calder IC, Yong AC, Woods RA, Crowe CA, Ham KN, Tange JD (1979) The nephrotoxicity of 4-aminophenol. II. The effect of metabolic inhibitors and inducers. Chem Biol Interact 27: 245–254
Crowe CA, Calder IC, Madsen NP, Funder CC, Green CR, Ham KN, Tange JD (1977) An experimental model of analgesic-induced renal damage — some effects ofp-aminophenol on rat kidney mitochondria. Xenobiotica 7: 345–356
Crowe CA, Yong AC, Calder IC, Harn KN, Tange JD (1979) The nephrotoxicity of 4-aminophenol. I. The effect on microsomal cytochromes, glutathione and covalent binding in kidney and liver. Chem Biol Interact 27: 235–243
Davis JM, Emslie KR, Sweet RS, Walker LL, Naughton RJ, Skinner SL, Tange JD (1983) Early functional and morphological changes in renal tubular necrosis due to 4-aminophenol. Kidney Int 24: 740–747
Davis ME (1988) Effects of AT-125 on the nephrotoxicity of hexachloro1,3-butadiene in rats. Toxicol Appl Pharmacol 95: 44–52
Eckert KG, Eyer P, Sonnenbichler J, Zetl I (1990) Activation and detoxification of aminophenols. II. Synthesis and structural elucidiation of various thiol addition products of 1,4-benzoquinoneimine and N-acetyl-1,4-benzoquinoneimine. Xenobiotica 20: 333 -350
Elfarra AA, Jacobson I, Anders MW (1986) Mechanism of S-(1,2-dichlorovinyl)glutathione-induced nephrotoxicity. Biochem Pharmacol 35: 283–288
Evelo CTA, Versteegh JFM, Blaauboer BJ (1984) Kinetics of the formation and secretion of the aniline metabolite 4-aminophenol and its conjugates by isolated rat hepatocytes. Xenobiotica 14: 409–416
Eyanagi R, Hisanari Y, Shigematsu H (1991) Studies of paracetamol/ phenacetin toxicity: isolation and characterization ofp-aminophenolglutathione conjugate. Xenobiotica 21: 793–803
Eyer P, Kampffmeyer H, Maister H, Rosch-Oehme E (1980) Biotransformation of nitrosobenzene, phenylhydroxylamine and aniline in the isolated perfused liver. Xenobiotica 10: 499–516
Finley KT (1974) The addition and substitution chemistry of quinones. In: Patai S (ed) The Chemistry of quinoid compounds Part II. John Wiley, London, pp 877–1144
Fowler LM (1992) Studies on the mechanism of nephrotoxicity of 4-aminophenol. PhD Thesis, Council for National Academic Awards
Fowler LM, Moore RB, Foster JR, Lock EA (1991) Nephrotoxicity of 4-aminophenol glutathione conjugate. Hum Exp Toxicol 10: 451–459
Gartland KPR, Bonner FW, Timbrell JA, Nicholson JK (1989) Biochemical characterisation of 4-aminophenol-induced nephrotoxic lesions in the F344 rat. Arch Toxicol 63: 97–106
Gartland KPR, Eason CT, Bonner FW, Nicholson JK (1990) Effects of biliary cannulation and buthionine sulphoximine pretreatment on the nephrotoxicity of para-aminophenol in the Fischer 344 rat. Arch Toxicol 64: 14–25
Gemborys MW, Mudge GH (1981) Formation and disposition of the minor metabolites of acetaminophen in the hamster. Drug Metab Dispos 9: 340–351
Green CR, Ham KN, Tange JD (1969) Kidney lesions induced in rats by 4-aminophenol. BMJ 1: 162–164
Job D, Dunford HB (1976) Substituent effect on the oxidation of phenols and aromatic amines by horseradish peroxidase compound I. Eur J Biochem 66: 607–614
Josephy PD, Eling TE, Mason RP (1982) Oxidation of 4-aminophenol catalysed by horseradish peroxidase and prostaglandin synthase. Mol Pharmacol 23: 461 -466
Kao J, Faulkner J, Bridges JW (1978) Metabolism of aniline in rats, pigs and sheep. Drug Metab Dispos 6: 549–555
Kiese M, Szincz L, Thiel N, Weger N (1975) Ferrihaemoglobin and kidney lesions in rats produced by 4-aminophenol or 4-dimethylaminophenol. Arch Toxicol 34: 337–340
Klos C, Koob M, Kramer C, Dekant W (1992)p-Aminophenol nephrotoxicity. Biosynthesis of toxic glutathione conjugates. Toxicol Appl Pharmacol 115: 98–106
Kozak EM, Tate SS (1982) Glutathione-degrading enzymes of microvillus membranes. J Biol Chem 257: 6322–6327
Lau SS, Jones TW, Highet RJ, Hill BA, Monks TJ (1990) Differences in the localization and extent of the renal proximal tubular necrosis caused by mercapturic acid and glutathione conjugates of 1,4-naphthoquinone and menadione. Toxicol Appl Pharmacol 104: 334–350
Lock EA, Ishmael J (1985) Effect of the organic acid transport inhibitor probenecid on renal cortical uptake and proximal tubular toxicity of hexachloro-1,3-butadiene and its conjugates. Toxicol Appl Pharmacol 81: 32–42
Lowry OH, Rosebrough NJ, Farr AL, Randell RJ (1951) Protein measurements with the folin-phenol reagent. J Biol Chem 193: 265–275
Meister A, Tate SS, Griffith OW (1981) γ-Glutamyltranspeptidase. Methods Enzymol 77: 237–242
Monks TJ, Lau SS (1990) Glutathione, γ-glutamyltransferase and the mercapturic acid pathway as modulators of 2-bromohydroquinone oxidation. Toxicol Appl Pharmacol 103: 557–563
Monks TJ, Highet RJ, Lau SS (1988) 2-Bromo-(diglutathion-S-yl) hydroquinone nephrotoxicity: physiological, biochemical and electrochemicals determinants. J Pharmacol Exp Ther 34: 283–288
McIntyre T, Curthoys NP (1982) Renal catabolism of glutathione. J Biol Chem 257: 11915–11921
Newton JF, Kuo C-H, Gemborys MWS, Mudge GH, Hook JB (1982) Nephrotoxicity of 4-aminophenol, a metabolite of acetaminophen in the Fischer 344 rat. Toxicol Appl Pharmacol 65: 336–344
Newton JF, Yoshimoto M, Bernstein J, Rush GF, Hook JB (1983) Acetaminophen nephrotoxicity in the rat. II. Strain differences in nephrotoxicity and metabolism of 4-aminophenol, a metabolite of acetaminophen. Toxicol Appl Pharmacol 69: 308–318
Paulson GD, Jacobsen AM, Still GG (1975) Animal metabolism of propham (isopropyl carbanilate): the rate of residues in alfalfa when consumed by rat and sheep. Pest Biochem Physiol 5: 523 -535
Pesce MA, Strande CS (1973) A new micromethod for determination of protein in cerebrospinal fluid and urine. Clin Chem 19: 1265–1267
Redegeld FAM, Hofman GA, Van de Loo PGF, Koster AS, Noordhoek J (1991) Nephrotoxicity of the glutathione conjugate of menadione (2-methyl-1,4-napthoquinone) in the isolated perfused rat kidney. Role of metabolism by γ-glutamyltranspeptidase and probenecidsensitive transport. J Pharmacol Exp Ther 256: 665–669
Smith GE, Griffiths LA (1976) Comparative metabolic studies of phenacetin and structurally-related compounds in the rat. Xenobiotica 6: 217–236
Szasz G (1969) A kinetic photometric method for serum γ-glutamyltranspeptidase. Clin Chem 15: 124–136
Tate SS, Meister A (1985) γ-Glutamyltranspeptidase from kidney. Methods Enzymol 113: 400–419
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Fowler, L.M., Foster, J.R. & Lock, E.A. Effect of ascorbic acid, acivicin and probenecid on the nephrotoxicity of 4-aminophenol in the Fischer 344 rat. Arch Toxicol 67, 613–621 (1993). https://doi.org/10.1007/BF01974068
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF01974068