title: Renal and hepatic toxicity of monochloroacetanilides in the Fischer 344 rat.
abstract: Chlorinated anilines are widely used chemical intermediates which have been shown to be nephrotoxicants and hepatotoxicants. A major metabolic pathway for the chloroanilines is via acetylation of the amino group to form chlorocetanilides. The purpose of this study was to examine the hepato- and nephrotoxic potential of the three monochloroacetanilides to determine if N-acetylation is an important biotransformation step for activation or detoxification of the chloroanilines in organ-directed toxicity. In one set of experiments, male Fischer 344 rats (4 rats/group) were injected intraperitoneally (i.p.) with a chloroacetanilide (CAA) (0.5, 1.0 or 1.5 mmol/kg) or vehicle and renal function monitored for 24 or 48 h. Liver function and tissue morphology also were determined at 24 or 48 h. None of the CAA were marked nephrotoxicants at doses of 0.5 or 1.0 mmol/kg. However, 4-CAA (1.5 mmol/kg) induced an increase in blood urea nitrogen concentration and kidney weight at 24 h and 3-CAA (1.5 mmol/kg) was lethal within 24 h. The decreasing order of in vivo nephrotoxic potential was found to be 4-CAA > or = 3-CAA > 2-CAA. Based on the elevation of ALT/GPT activity at 48 h, the order of hepatotoxic potential was found to be 4-CAA > 3-CAA, 2-CAA. In a second set of experiments, the in vitro effect of the chloroacetanilides on organic ion transport by renal cortical slices was examined. Both 3- and 4-CAA decreased organic ion accumulation at bath concentrations of 10(-5) M or greater, while 2-CAA had no effect at concentrations up to 10(-3) M. These results demonstrate that the order of nephrotoxic and hepatotoxic potential among the chloroacetanilide isomers is different than among the chloroanilines and that the chloroacetanilides were generally less potent as hepatotoxicants or nephrotoxicants than the corresponding chloroaniline. In addition, N-acetylation appears to be a detoxification rather than a bioactivation step in chloroaniline-induced liver or kidney injury.
authors.affiliation: Department of Pharmacology, Marshall University School of Medicine, Huntington, WV 25755.
authors.forename: G O
authors.initials: GO
authors.lastname: Rankin
authors.forename: M A
authors.initials: MA
authors.lastname: Valentovic
authors.forename: K W
authors.initials: KW
authors.lastname: Beers
authors.forename: D W
authors.initials: DW
authors.lastname: Nicoll
authors.forename: J G
authors.initials: JG
authors.lastname: Ball
authors.forename: D K
authors.initials: DK
authors.lastname: Anestis
authors.forename: P I
authors.initials: PI
authors.lastname: Brown
authors.forename: J L
authors.initials: JL
authors.lastname: Hubbard
mesh_terms: D000107:Acetylation; D000410:Alanine Transaminase / Q000097:blood; D000814:Aniline Compounds / Q000633:toxicity*; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D004326:Drinking / Q000187:drug effects; D004435:Eating / Q000187:drug effects; D007668:Kidney / Q000187:drug effects* / Q000201:enzymology; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D009929:Organ Size / Q000187:drug effects; D051381:Rats; D011916:Rats, Inbred F344
chemical_list: D000814:Aniline Compounds; C031392:3-chloroaniline; D000410:Alanine Transaminase; C025257:2-chloroaniline; C004658:4-chloroaniline