On the mechanisms of the CCl4-induced inhibition of liver cytochrome P-450.

The role of covalent binding of CCl4 radicals to the microsomal protein in the CCl4-induced inhibition of cytochrome P-450 was investigated. The incubation of liver microsomes with NADPH and CCl4 under anaerobic conditions (to avoid lipid peroxidation) results in an inhibition of cytochrome P-450 similar to that observed in the in vivo intoxication with a standard dose (0.25 ml/100 g body wt) of CCl4, when the level of covalent binding is 5-10 fold higher than that observed in the in vivo condition. When in the in vitro experiments the level of covalent binding is of the same magnitude as that observed in vivo, minimal if any inhibition of cytochrome P-450 is seen. Experiments carried out under aerobic conditions seem to indicate that the CCl4-induced inhibition of cytochrome P-450 depends more on lipid peroxidation than on covalent binding.