Chemical modulation of early carbon tetrachloride liver injury

Abstract

Insight into the mechanism of the toxic interaction of CCl 4 with liver endoplasmic reticulum was sought through modulation of the early in vivo effects of CCl 4 by agents which either inhibit its binding with cytochrome P-450 or have free radical sequestering and/or antioxidant activities. Alterations in known parameters of CCl 4 injury were compared between respective control and experimental groups of animals receiving β-diethylaminoethyl-3,3′-diphenylpropyl acetate (SKF 525A), 10-(2-dimethylaminopropyl)phenothiazine (promethazine), N,N′-diphenyl- p-phenylenediamine (DPPD), α-tocopherol acetate, or ethylenediamine-tetraacetic acid (EDTA). The extent of suppression of glucose-6-phosphatase staining (G-6-Pase) and increase in stainable calcium were examined at 1 hr, and lipid conjugated diene contents, NADPH-NT reductase, glucose-6-phosphatase and oxidative N-demethylase activities of microsomes, in vivo protein synthesis and cell sap RNA were determined 2 hr after poisoning with 26 mmol CCl 4/kg rat. All modulating agents wholly or partially prevented loss of in vivo protein synthesis 2 hr after CCl 4. In addition, DPPD and α-tocopherol reduced the extent of histochemically demonstrable G-6-Pase suppression and blocked the appearance of stainable calcium. SKF 525A pretreatment which reduced oxidative N-demethylase activity of liver endoplasmic reticulum also moderated the increase in lipid-conjugated diene following CCl 4. But SKF 525A was without effect on the magnitude of loss of histochemically determined G-6-Pase or the influx of stainable calcium following poisoning. The qualitative differences between the effects of SKF 525A and α-tocopherol on CCl 4-induced changes in liver endoplasmic reticulum indicate that the chlorocarbon may interact at two or more loci in the membrane.