Inhibition of the high affinity Ca²⁺-ATPase activity in rat liver plasma membranes following carbon tetrachloride intoxication

In vivo administration of CCl₄ (2.5 ml/kg, body wt.) to rats results in an early and then progressive inhibition of the high affinity Ca²⁺-ATPase activity in rat liver plasma membranes. The derangement to the Ca²⁺-ATPase seems to be independent on a 'solvent effect' of the agent since the in vitro addition of increasing concentrations of either CCl₄ or ethanol to control plasma membranes does not affect the enzymatic activity. By using the technique of vitamin E pretreatment of experimental animals we show that the damage to the Ca²⁺-ATPase seems to follow a two-step kinetics. The early inhibition of the enzyme is not prevented by α-tocopherol supplementation and seems then unrelated to lipid peroxidative processes. The same procedure is however able to affort a significant protection against the exacerbation of the damage to the Ca²⁺-ATPase becoming evident late during the course of CCl₄ intoxication. The high affinity Ca²⁺-ATPase is affected in vitro by 4-hydroxy-nonenal (HNE), a major end-product of lipid peroxidation interacting with -SH groups. Similar results were obtained after the addition to the incubation medium of sulphydryl reagents. The possible mechanisms involved in Ca²⁺-ATPase inhibition are discussed in relation to the development of CCl₄ toxicity and to the role of lipid peroxidative processes.