The inhibitory effects in vitro of phenothiazines and other drugs on lipid-peroxidation systems in rat liver microsomes, and their relationship to the liver necrosis produced by carbon tetrachloride

摘要

p1. The effects of several phenothiazine derivatives on lipid-peroxidation systems in rat liver microsomes were studied and the results are considered in relation to the hepatotoxic action of carbon tetrachloride. 2. The lipid-peroxidation system coupled to NADPHsub2/sub oxidation and stimulated by an ADP–Fesup2+/sup mixture is strongly inhibited iin vitro/i by promethazine (50% inhibition at 29μm). Chlorpromazine and Stelazine also inhibit the peroxidation system but are less effective than promethazine. 3. The effects of promethazine on three other systems involving oxygen uptake (sulphite oxidation, orcinol oxidation and mitochondrial succinate oxidation) were also studied. Promethazine does not inhibit these systems to the same extent as it does the NADPHsub2/sub–ADP–Fesup2+/sup lipid-peroxidation system. 4. Promethazine also produces an inhibition of the NADPHsub2/sub–ADP–Fesup2+/sup system in liver microsomes after administration iin vivo/i. It is concluded that the inhibition involves the interaction of the drug (or a metabolite of it) with the microsomal electron-transport chain. 5. Several other compounds known to protect the rat against liver necrosis after the administration of carbon tetrachloride were tested for inhibitory action on the NADPHsub2/sub–ADP–Fesup2+/sup system. No clear correlation was observed between effectiveness iin vivo/i as a protective agent and inhibitory effects on the NADPHsub2/sub–ADP–Fesup2+/sup system iin vitro/i. 6. Promethazine was found to inhibit the stimulation of lipid peroxidation produced in rat liver microsomes by low concentrations of carbon tetrachloride. This effect occurs at a concentration similar to that observed iin vivo/i after administration of a normal clinical dose./p