4-Amino-2,6-dichlorophenol nephrotoxicity in the Fischer 344 rat: protection by ascorbic acid, AT-125, and aminooxyacetic acid.
A halogenated derivative of 4-aminophenol, 4-amino-2, 6-dichlorophenol (ADCP), is a potent nephrotoxicant and a weak hepatotoxicant in Fischer 344 rats. Although the mechanism of ADCP nephrotoxicity is unknown, ADCP could undergo oxidation to a reactive intermediate, such as a 4-amino-2,6-dichlorophenoxy radical or 2,6-dichloro-1,4-benzoquinoneimine, which can generate additional free radicals and/or covalently bind to cellular proteins. The toxic process might also be mediated by glutathione (GSH) conjugates of ADCP, as suggested for the mechanism of 4-aminophenol nephrotoxicity. In this study, the effects of modulators of oxidation and GSH conjugation-related metabolism or transport on ADCP-induced nephrotoxicity were examined. In one set of experiments, male Fischer 344 rats (four/group) were intraperitoneally (ip) administered ADCP (0.38 mmol/kg) only or coadministered an antioxidant, ascorbic acid (1.14 mmol/kg, ip) with ADCP. Administration of ascorbic acid markedly reduced both functional nephrotoxicity and morphological changes induced by ADCP. Administration of a gamma-glutamyltransferase (GGT) inhibitor, l-(alphaS, 5S)-alpha-amino-3-chloro-4,5-dihydroxy-5-isoxazoleacetic acid (10 mg/kg, ip), or a cysteine conjugate beta-lyase inhibitor, aminooxyacetic acid (0.5 mmol/kg, ip), 1 hr before ADCP (0.38 mmol/kg) challenge partially protected rats against ADCP nephrotoxicity. In contrast, administration of an organic anion transport inhibitor, probenecid (140 mg/kg, ip), 30 min before ADCP had little effect on ADCP nephrotoxicity. The GSH depletor, buthionine sulfoximine (890 mg/kg, ip), was given 2 hr prior to ADCP and only minimal protection was noted. In addition, the nonprotein sulfhydryl (NPSH) contents in renal cortex and liver were determined at 2 hr following the administration of ADCP only or ascorbic acid/ADCP. Ascorbic acid afforded complete prevention of the depletion of NPSH in the kidney and liver caused by ADCP administration and also prevented the elevation of renal glutathione disulfide content induced by ADCP. The results indicate that oxidation of ADCP appears to be essential to ADCP nephrotoxicity and that GSH or GSH-derived conjugates of ADCP may be partly responsible for the nephrotoxic effects of ADCP via a GGT-mediated mechanism.
Hong
S K
SK
Department of Pharmacology, Marshall University School of Medicine, Huntington, West Virginia 25704-9388, USA.
Anestis
D K
DK
Ball
J G
JG
Valentovic
M A
MA
Brown
P I
PI
Rankin
G O
GO
D000625:Aminooxyacetic Acid / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D001205:Ascorbic Acid / Q000494:pharmacology*; D019328:Buthionine Sulfoximine / Q000494:pharmacology; D002733:Chlorophenols / Q000008:administration & dosage / Q000633:toxicity*; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005978:Glutathione / Q000378:metabolism; D007274:Injections, Intraperitoneal; D007555:Isoxazoles / Q000494:pharmacology; D007672:Kidney Cortex / Q000187:drug effects* / Q000473:pathology; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008297:Male; D011339:Probenecid / Q000494:pharmacology; D051381:Rats; D011916:Rats, Inbred F344; D013438:Sulfhydryl Compounds / Q000378:metabolism; D005723:gamma-Glutamyltransferase / Q000037:antagonists & inhibitors*
D000975:Antioxidants; D002733:Chlorophenols; D004791:Enzyme Inhibitors; D007555:Isoxazoles; D013438:Sulfhydryl Compounds; D000625:Aminooxyacetic Acid; D019328:Buthionine Sulfoximine; C088160:4-amino-2,6-dichlorophenol; D005723:gamma-Glutamyltransferase; D005978:Glutathione; C006303:acivicin; D011339:Probenecid; D001205:Ascorbic Acid