Nephrotoxicity of 4-amino-2-chlorophenol and 2-amino-4-chlorophenol in the Fischer 344 rat.
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.
Hong
S K
SK
Department of Pharmacology, Marshall University School of Medicine, Huntington, WV 25704-9388, USA.
Valentovic
M A
MA
Anestis
D K
DK
Ball
J G
JG
Brown
P I
PI
Rankin
G O
GO
D000627:Aminophenols / Q000008:administration & dosage / Q000633:toxicity*; D000818:Animals; D001806:Blood Urea Nitrogen; D002733:Chlorophenols / Q000008:administration & dosage / Q000633:toxicity*; D005943:Gluconeogenesis / Q000187:drug effects; D006029:Glycosuria / Q000139:chemically induced; D007274:Injections, Intraperitoneal; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism; D007672:Kidney Cortex / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008297:Male; D011507:Proteinuria / Q000139:chemically induced; D051381:Rats; D011916:Rats, Inbred F344; D013329:Structure-Activity Relationship
D000627:Aminophenols; D002733:Chlorophenols; C027296:2-amino-4-chlorophenol; C013877:3-chloro-4-hydroxyaniline; D007770:L-Lactate Dehydrogenase