Late preventive effects of quinacrine on carbon tetrachloride induced liver necrosis.
We have previously reported that treatments stimulating phospholipid (PL) synthesis or preventing PL degradation were late preventive agents against CCl4-induced liver necrosis. Later studies by others postulated that stimulation of phospholipase A2 (PLA2) plays a role in PL degradative processes responsible for CCl4 damage. Quinacrine (QUIN) is a well known inhibitor of PLA2. In this work we report that QUIN (150 mg/kg i.p.) partially prevents CCl4-induced liver necrosis at 24 h when given 30 min before or 6 or 10 h after CCl4 (2.5 ml/kg p.o.) QUIN administration does not modify at 1 or 3 h after poisoning CCl4 levels reaching the liver, covalent binding of CCl4 reactive metabolites to proteins or lipids, CCl4-induced lipid peroxidation process, CCl4-induced decreases in body temperature, or glutathione levels in liver. QUIN concentrations in liver at times from 1 to 24 h are well over those required to inhibit PLA2 activity. Results are compatible with the hypothesis that CCl4 activation of PLA2 at late stages of poisoning plays a role in CCl4-induced liver necrosis.
González Padrón
A
A
Centro de Investigaciones Toxicológicas (CEITOX) CITEFA/CONICET, Buenos Aires, Argentina.
de Toranzo
E G
EG
Castro
J A
JA
D000818:Animals; D001831:Body Temperature / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D002250:Carbon Radioisotopes; D002251:Carbon Tetrachloride / Q000378:metabolism / Q000633:toxicity*; D056486:Chemical and Drug Induced Liver Injury; D005978:Glutathione / Q000378:metabolism; D050356:Lipid Metabolism; D015227:Lipid Peroxidation / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D008107:Liver Diseases / Q000378:metabolism / Q000517:prevention & control*; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D009336:Necrosis / Q000139:chemically induced; D010741:Phospholipases A / Q000378:metabolism; D054467:Phospholipases A2; D010743:Phospholipids / Q000378:metabolism; D011485:Protein Binding; D011506:Proteins / Q000378:metabolism; D011796:Quinacrine / Q000378:metabolism / Q000493:pharmacokinetics / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors
D002250:Carbon Radioisotopes; D010743:Phospholipids; D011506:Proteins; D002251:Carbon Tetrachloride; D010741:Phospholipases A; D054467:Phospholipases A2; D005978:Glutathione; D011796:Quinacrine; D002118:Calcium