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Effect of inhibitors of drug metabolizing enzymes on carbon tetrachloride hepatotoxicity

1971; Elsevier BV; Volume: 18; Issue: 3 Linguagem: Inglês

10.1016/s0041-008x(71)80017-0

1096-0333

Elida V. Cignoli, José Alberto Castro,

Pharmacology and Obesity Treatment

Several inhibitors of drug metabolizing enzymes were tested for their ability to prevent carbon tetrachloride-induced liver necrosis and fatty infiltration in the rat. CFT 1201, Sch 5705, Sch 5706, Sch 5712, and Lilly 18947 protected against necrosis to some extent. CFT 1201 and Sch 5706 were the most effective compounds. CFT 1201 also significantly prevented the fatty infiltration. DPEA and imipramine were unable to prevent necrosis. The preventive action of inhibitors of drug metabolizing enzymes against necrosis cannot be ascribed solely to their ability to inhibit either drug metabolism or lipid peroxidation, since imipramine was the most potent inhibitor of lipid peroxidation and it was not effective as a protector. Moreover, Sch 5706 was the most effective compound tested, and it neither inhibited carbon tetrachloride-induced lipid peroxidation nor prolonged the pentobarbital sleeping time of rats more than did the other compounds. The protective effect found by administration of a substrate of drug metabolizing enzymes such as aminopyrine suggests that part of the overall preventive effect of the inhibitors might be due to a substrate-like action competing with lipid peroxidation for TPNH and oxygen. Other factors like interference with gastrointestinal absorption or production of hypothermia could also be important.