Aminophenols and halogenated
anilines induce nephrotoxicity and mild hepatotoxicity in rats. In this study, the in vivo and in vitro nephrotoxic potential of
4-amino-2-chlorophenol and
2-amino-4-chlorophenol, monochlorinated
aminophenols and potential metabolites of
3-chloroaniline, was evaluated. Hepatotoxicity of both compounds was also examined in vivo. Male Fischer 344 rats (four/group) were administered
4-amino-2-chlorophenol hydrochloride (0.4, 0.8 or 1.0 mmol/kg),
2-amino-4-chlorophenol hydrochloride (0.4, 0.8 or 1.2 mmol/kg) or vehicle intraperitoneally (i.p.) and renal and hepatic function monitored for 48 h. Administration of
4-amino-2-chlorophenol (0.8 mmol/kg) induced nephrotoxicity, while only minor changes in kidney function were observed following administration of 0.4 mmol/kg of
4-amino-2-chlorophenol or 0.8 mmol/kg of
2-amino-4-chlorophenol. Increasing the dose of
4-amino-2-chlorophenol to 1.0 mmol/kg or
2-amino-4-chlorophenol to 1.2 mmol/kg resulted in lethality. Nephrotoxicity induced by
4-amino-2-chlorophenol was characterized by diuresis, increased
proteinuria, glucosuria,
hematuria, elevated blood
urea nitrogen (BUN) concentration and kidney weight, and marked proximal tubular damage, while
2-amino-4-chlorophenol induced milder effects on renal function and transient
oliguria instead of diuresis. No hepatotoxicity was observed with either compound at any dose tested. In the in vitro studies, the direct effects of
4-amino-2-chlorophenol or
2-amino-4-chlorophenol on organic ion accumulation,
pyruvate-stimulated gluconeogenesis and
lactate dehydrogenase (LDH) leakage were determined using renal cortical slices.
4-Amino-2-chlorophenol and
2-amino-4-chlorophenol were almost equally effective in inhibiting organic
anion or
cation uptake and gluconeogenesis or increasing LDH leakage, although small differences in the minimum effective concentrations were present (minimum effective concentration, 0.01-0.5 mM range). These results demonstrate that
4-amino-2-chlorophenol is a more potent nephrotoxicant than
2-amino-4-chlorophenol in vivo. The results also indicate that the addition of a
chloride group to
aminophenols enhances renal toxicity.