Late protective effects of the anticalmodulin drug fluphenazine on carbon tetrachloride-induced liver necrosis.
Fluphenazine (FP) treatment (50 mg/kg bw, ip in saline) 30 min before or 6 or 10 h after CCl4 administration (1 ml/kg ip in olive oil) significantly prevented the liver necrosis produced by the hepatotoxin at 24 h. FP had enhancing effects on the covalent binding of CCl4 reactive metabolites to cellular constituents and on CCl4 induced lipid peroxidation. FP lowered body temperature of the CCl4-poisoned animals during the 24 h observation period. The obtained results are compatible but do not prove the hypothesis that calmodulin (CaM) had participation in late occurring events preceding necrosis. FP lowering action on body temperature, however, might also play a role in the effects of this drug on the onset of CCl4 induced liver necrosis. FP levels in liver tissue as determined by gas chromatography-mass spectrometry evidenced the presence of the drug in amounts sufficient to inhibit CaM and that suggests that not all preventive effects of FP are due to its indirect actions on the central nervous system via decreased body temperature.
de Ferreyra
E C
EC
Centro de Investigaciones Toxicológicas (CEITOX)-CITEFA/CONICET, Zufriategui, Buenos Aires, Argentina.
Bernacchi
A S
AS
San Martin
M F
MF
Castro
G D
GD
Castro
J A
JA
D000818:Animals; D001833:Body Temperature Regulation / Q000187:drug effects; D002147:Calmodulin / Q000037:antagonists & inhibitors*; D002251:Carbon Tetrachloride / Q000633:toxicity*; D056486:Chemical and Drug Induced Liver Injury; D005476:Fluphenazine / Q000032:analysis / Q000494:pharmacology / Q000627:therapeutic use*; D008401:Gas Chromatography-Mass Spectrometry; D015227:Lipid Peroxidation; D008107:Liver Diseases / Q000188:drug therapy / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D009336:Necrosis; D051381:Rats; D017207:Rats, Sprague-Dawley
D002147:Calmodulin; D002251:Carbon Tetrachloride; D005476:Fluphenazine