title: Nephrotoxic potential of 2-amino-5-chlorophenol and 4-amino-3-chlorophenol in Fischer 344 rats: comparisons with 2- and 4-chloroaniline and 2- and 4-aminophenol.
abstract: Nephrotoxicity occurs following intraperitoneal (i.p.) administration of 2-chloroaniline or 4-chloroaniline hydrochloride to Fischer 344 rats, but the nephrotoxicant chemical species and mechanism of nephrotoxicity are unknown. The purpose of this study was to evaluate the in vivo and in vitro nephrotoxic potential of 2-amino-5-chlorophenol and 4-amino-3-chlorophenol, metabolites of 4-chloroaniline and 2-chloroaniline. A comparison was also made between the nephrotoxic potential of the aminochlorophenols and the corresponding aminophenols to examine the effect of adding a chloride group on the nephrotoxic potential of the animophenols. Male Fischer 344 rats (4/group) were given an i.p. injection of a chloroaniline or aminochlorophenol hydrochloride (1.5 mmol/kg), and aminophenol (1.0 or 1.5 mmol/kg), or vehicle, and renal function monitored at 24 and 48 h. Both aminochlorophenols induced smaller and fewer renal effects that the parent chloroanilenes in vivo. Also, 4-aminophenol was markedly more potent as a nephrotoxicant that 4-amino-3-chlorophenol, while 2-aminophenol and 2-amino-5-chlorophenol induced only mild change in renal function. In vitro, the phenolic compounds reduce p-aminohippurate accumulation by renal cortical slices at bath concentrations of 0.01 mM, while a bath concentration of 0.50 mM or greater was required for the chloroanilines. However, all compounds reduced tetraethylammonium accumulation at bath concentrations of 0.1-0.5 mM or greater. These results indicate that extrarenally-produced aminochlorophenol metabolites do not contribute to the mechanism of chloroaniline nephrotoxicity. Also, the reduced nephrotoxic potential of 4-amino-3-chlorophenol compared to 4-aminophenol could result from an altered ability of the aminochlorophenol to redox cycle or form conjugates.
authors.affiliation: Department of Pharmacology, Marshall University, Huntington, West Virginia 25704-9388, USA.
authors.forename: G O
authors.initials: GO
authors.lastname: Rankin
authors.forename: K W
authors.initials: KW
authors.lastname: Beers
authors.forename: D W
authors.initials: DW
authors.lastname: Nicoll
authors.forename: D K
authors.initials: DK
authors.lastname: Anestis
authors.forename: S K
authors.initials: SK
authors.lastname: Hong
authors.forename: J L
authors.initials: JL
authors.lastname: Hubbard
authors.forename: J G
authors.initials: JG
authors.lastname: Ball
authors.forename: M A
authors.initials: MA
authors.lastname: Valentovic
authors.forename: P I
authors.initials: PI
authors.lastname: Brown
mesh_terms: D000627:Aminophenols / Q000633:toxicity; D000814:Aniline Compounds / Q000633:toxicity; D000818:Animals; D002733:Chlorophenols / Q000008:administration & dosage / Q000633:toxicity*; D007274:Injections, Intraperitoneal; D007668:Kidney / Q000187:drug effects*; D007677:Kidney Function Tests; D008297:Male; D009929:Organ Size / Q000187:drug effects; D051381:Rats; D011916:Rats, Inbred F344
chemical_list: D000627:Aminophenols; D000814:Aniline Compounds; D002733:Chlorophenols; C099674:4-amino-3-chlorophenol; C027667:2-aminophenol; C099673:2-amino-5-chlorophenol; C025257:2-chloroaniline; C026729:4-aminophenol; C004658:4-chloroaniline