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 Fische r 344 rats. Although the mechanism of ADCP nephrotoxicity is unknown, ADCP could undergo oxidation to a reactive intermediate, such as a 4-a mino-2,6-dichlorophenoxy radical or 2,6-dichloro-1,4-benzoquinoneimine , which can generate additional free radicals and/or covalently bind t o cellular proteins. The toxic process might also be mediated by gluta thione (GSH) conjugates of ADCP, as suggested for the mechanism of 4-a minophenol 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) administere d ADCP (0.38 mmol/kg) only or coadministered an antioxidant, ascorbic acid (1.14 mmol/kg, ip) with ADCP. Administration of ascorbic acid mar kedly reduced both functional nephrotoxicity and morphological changes induced by AMCP. Administration of a gamma-glutamyltransferase (GGT) inhibitor, L-(alpha S, pha-amino-3-chloro-4,5-dihydroxy-5-isoxazoleace tic 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 c ontrast, administration of an organic anion transport inhibitor, probe necid (140 mg/kg, ip), 30 min before ADCP had little effect on ADCP ne phrotoxicity. 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 ADC P only or ascorbic acid/ADCP. Ascorbic acid afforded complete preventi on of the depletion of NPSH in the kidney and liver caused by ADCP adm inistration and also prevented the elevation of renal glutathione disu lfide content induced by ADCP. The results indicate that oxidation of ADCP appears to be essential to ADCP nephrotoxicity and that GSH or GS H-derived conjugates of ADCP may be partly responsible for the nephrot oxic effects of ADCP via a GGT-mediated mechanism. (C) 1997 Academic P ress.