Modulation of the course of CCl4-induced liver injury by the anti-calmodulin drug thioridazine.
Thioridazine (TDZ) administration to rats (50 mg/kg i.p.) 6 or 10 h after CCl4 treatment (1 ml/kg in olive oil i.p.) partially prevented necrogenic effects of this compound at 24 h but not at 72 h. TDZ did not have inhibitory effects on CCl4 activation, covalent binding (CB) of reactive metabolites to cellular constituents or CCl4-induced lipid peroxidation (LP). Moreover, TDZ had enhancing effects on both LP and CB. TDZ was able to increase protein and phospholipid synthesis and slightly but significantly enhanced protein but not phospholipid degradation in livers from control rats. TDZ administration decreased calcium liver content in CCl4-poisoned animals but did not change the intensity of CCl4-induced fatty liver. TDZ lowered body temperature in CCl4-treated animals during the 24 h observation period. These results and previous studies from our laboratory suggest calcium and calmodulin (CaM) participation in the CCl4 necrogenic effects on the liver but not in the hepatotoxin-induced fatty liver. TDZ-lowering effects on body temperature might also be a determinant in the delaying effects of this drug on the onset of CCl4-induced necrosis. Present experiments did allow discrimination between these two or other possible mechanisms for TDZ modulation effects.
Villarruel
M C
MC
Centro de Investigaciones Toxicológicas (CEITOX), CITEFA/CONICET, Villa Martelli, Argentina.
Fernández
G
G
de Ferreyra
E C
EC
de Fenos
O M
OM
Castro
J A
JA
D000818:Animals; D002118:Calcium / Q000378:metabolism; D002147:Calmodulin / Q000037:antagonists & inhibitors*; D002251:Carbon Tetrachloride / Q000633:toxicity*; D002252:Carbon Tetrachloride Poisoning / Q000378:metabolism* / Q000473:pathology; D004357:Drug Synergism; D005234:Fatty Liver / Q000139:chemically induced / Q000473:pathology; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects* / Q000378:metabolism; D010743:Phospholipids / Q000096:biosynthesis; D011506:Proteins / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D013881:Thioridazine / Q000008:administration & dosage / Q000494:pharmacology*
D002147:Calmodulin; D010743:Phospholipids; D011506:Proteins; D002251:Carbon Tetrachloride; D013881:Thioridazine; D002118:Calcium