Effect of ascorbic acid, acivicin and probenecid on the nephrotoxicity of 4-aminophenol in the Fischer 344 rat.
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)
Fowler
L M
LM
Zeneca Central Toxicology Laboratory, Nr. Macclesfield, Cheshire, UK.
Foster
J R
JR
Lock
E A
EA
D000627:Aminophenols / Q000493:pharmacokinetics / Q000633:toxicity*; D000818:Animals; D000963:Antimetabolites / Q000494:pharmacology*; D001205:Ascorbic Acid / Q000494:pharmacology*; D007555:Isoxazoles / Q000494:pharmacology*; D007668:Kidney / Q000187:drug effects / Q000473:pathology; D007674:Kidney Diseases / Q000139:chemically induced* / Q000473:pathology; D007677:Kidney Function Tests; D008099:Liver / Q000187:drug effects; D008297:Male; D011339:Probenecid / Q000494:pharmacology*; D051381:Rats; D011916:Rats, Inbred F344
D000627:Aminophenols; D000963:Antimetabolites; D007555:Isoxazoles; C006303:acivicin; D011339:Probenecid; D001205:Ascorbic Acid; C026729:4-aminophenol