Prevention of carbon tetrachloride-induced necrosis by inhibitors of drug metabolism—Further studies on their mechanism of action

Abstract

Liver necrosis caused by CCl 4 is known to be decreased by the administration of SKF 525-A (2-diethylaminoethyl 2,2-diphenylvalerate), Sch 5705 (ethyl 2-diethyl-aminoethyl-2-phenyl-2-ethyl malonate), Sch 5706 [ethyl N-(2-diethylaminoethyl) 2-phenyl-2-ethyl malonate], Sch 5712 (ethyl 2-diethylaminoethyl 2-ethyl-2-butyl malonate), CFT 1201 [2-diethylaminoethyl 2-phenyl (2-propene) 4-penten-1-oate], Lilly 18947 (2,4-dichloro-6-phenyl phenoxyethyl diethylamine) and DPEA (2,4-dichloro-6-phenyl phenoxyethylamine). Although these substances are known to inhibit cytochrome P-450 dependent drug-metabolizing enzymes in liver microsomes, they apparently do not evoke their protective effects by slowing the elimination of CCl 4. In fact, SKF 525-A, but none of the other inhibitors, partially prevents the impairing effects of CCl 4 on cytochrome P-450 in liver. Although SKF 525-A markedly decreased the liver necrosis and the rise in serum isocitrate dehydrogenase (ICD) caused by CCl 4, it only partially prevented the CCl 4-induced decrease in body temperature.