IN-VIVO AND IN-VITRO 4-AMINO-2,6-DICHLOROPHENOL NEPHROTOXICITY AND HEPATOTOXICITY IN THE FISCHER-344 RAT

Halogenated anilines and aminophenols are nephrotoxicants and hepatoto xicants in mammals. The purpose of this study was to determine the in vivo and in vitro nephrotoxic and hepatotoxic potential of 4-amino-2,6 -dichlorophenol, a putative metabolite of 3,5-dichloroaniline. In the in vivo experiments, male Fischer 344 rats (four/group) were administe red a single intraperitoneal (i.p.) injection of 4-amino-2,6-dichlorop henol (0.25, 0.38 or 0.50 mmol/kg) or vehicle (dimethylsulfoxide (DMSO ), 1.0 ml/kg) and renal and hepatic function monitored for 48 h. Only minor changes in function or morphology were observed in the 0.25 mmol /kg treatment group. However, in the 0.38 mmol/kg treatment group evid ence of both nephrotoxicity and hepatotoxicity were evident. Nephrotox icity was characterized by increased proteinuria, glucosuria, hematuri a, elevated blood urea nitrogen (BUN) concentration and kidney weight, decreased p-aminohippurate (PAH) accumulation and proximal tubular ne crosis in the corticomedullary region of the kidney. Hepatotoxicity wa s characterized by elevated plasma alanine aminotransferase (ALT/GPT) activity and liver weight. Animals administered the 0.5 mmol/kg dose d ied within 24 h. In the in vitro experiments, the effect of 4-amino-2, 6-dichlorophenol on organic ion accumulation, gluconeogenesis and lact ate dehydrogenase (LDH) leakage was quantitated in liver and/or renal cortical slices. Organic anion accumulation was inhibited in renal cor tical slices by 4-amino-2,6-dichlorophenol bath concentrations of 5 x 10(-6) M or higher, while organic cation uptake was decreased at 4-ami no-2,6-dichlorophenol bath concentrations of 1 x 10(-5) M or greater. Renal and hepatic pyruvate-stimulated gluconeogenesis were inhibited a nd renal LDH leakage increased at 4-amino-2,6-dichlorophenol bath conc entrations of 5 x 10(-5) M or greater. Increased LDH leakage from live r slices was not observed. These results demonstrate that 4-amino-2,6- dichlorophenol is a nephrotoxicant and hepatotoxicant in vivo and in v itro and that the kidney is more susceptible to 4-amino-2,6-dichloroph enol toxicity than the liver.