title: Nephrotoxicity of chlorofluoroacetic acid in rats.
abstract: Dichloroacetic acid (DCA), chlorofluoroacetic acid (CFA), and difluoroacetic acid (DFA) are inhibitors of pyruvate dehydrogenase kinase. DCA is used for the clinical management of congenital lactic acidosis. Glutathione transferase zeta (GSTZ1-1) catalyzes the biotransformation of DCA and CFA, and DCA is a mechanism-based inactivator of GSTZ1-1. In rodents, DCA causes multiorgan toxicities and is hepatocarcinogenic. The toxic effects of CFA, which is an excellent substrate but a poor inactivator of GSTZ1-1, have not been investigated. The objective of this study was to investigate the nephrotoxicity of CFA. Rats given a single dose of 1.5 mmol/kg CFA became anuric and died within 24 h. Urinalysis and light microscopic analysis showed that rats given 0.6-1.2 mmol/kg CFA developed polyuria, glycosuria, and renal proximal tubular damage. Electron microscopic analysis indicated a role for apoptosis in CFA-induced cell death. The nephrotoxicity of CFA was associated with a dose-dependent increase in inorganic fluoride excretion. Treatment of rats with DCA for 5 days to inactivate GSTZ1-1 failed to prevent metabolism of CFA to fluoride and did not block CFA-induced renal damage. A role for GSTZ1-1-catalyzed release of fluoride from CFA is proposed but a role for other enzymes cannot be excluded. DFA, which is not metabolized to fluoride by GSTZ1-1, was given to rats as a control and was also nephrotoxic: rats given 1.2 mmol DFA/kg/day for 5 days had normal urine volumes but showed proximal and distal tubular damage; fluoride excretion was not elevated. The mechanism of DFA-induced nephrotoxicity is not known but appears to differ from that of CFA.
authors.affiliation: Department of Pharmacology and Physiology and Laboratory of Animal Medicine, University of Rochester Medical Center, 601 Elmwood Ave, Box 711, Rochester, New York 14642, USA.
authors.forename: Hoffman B M
authors.initials: HB
authors.lastname: Lantum
authors.forename: Raymond B
authors.initials: RB
authors.lastname: Baggs
authors.forename: Daria M
authors.initials: DM
authors.lastname: Krenitsky
authors.forename: M W
authors.initials: MW
authors.lastname: Anders
mesh_terms: D000085:Acetates / Q000378:metabolism / Q000633:toxicity*; D000818:Animals; D003999:Dichloroacetic Acid / Q000378:metabolism / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D005459:Fluorides / Q000097:blood / Q000652:urine; D005463:Fluoroacetates / Q000378:metabolism / Q000633:toxicity; D005982:Glutathione Transferase / Q000378:metabolism; D007274:Injections, Intraperitoneal; D007668:Kidney / Q000187:drug effects* / Q000201:enzymology / Q000648:ultrastructure; D008099:Liver / Q000201:enzymology; D008297:Male; D008854:Microscopy, Electron; D051381:Rats; D011916:Rats, Inbred F344; D013997:Time Factors; D016482:Urinalysis
chemical_list: D000085:Acetates; D005463:Fluoroacetates; C120963:chlorofluoroacetic acid; D003999:Dichloroacetic Acid; C498692:Gstz1 protein, rat; D005982:Glutathione Transferase; D005459:Fluorides; C027495:difluoroacetic acid