Carbon tetrachloride-mediated lipid peroxidation induces early mitochondrial alterations in mouse liver

Abstract

Although carbon tetrachloride (CCl 4 )-induced acute and chronic hepatotoxicity have been extensively studied, little is known about the very early in vivo effects of this organic solvent on oxidative stress and mitochondrial function. In this study, mice were treated with CCl 4 (1.5 ml/kg ie 2.38 g/kg) and parameters related to liver damage, lipid peroxidation, stress/defense and mitochondria were studied 3 h later. Some CCl 4 -intoxicated mice were also pretreated with the cytochrome P450 2E1 inhibitor diethyldithiocarbamate or the antioxidants Trolox C and dehydroepiandrosterone. CCl 4 induced a moderate elevation of aminotransferases, swelling of centrilobular hepatocytes, lipid peroxidation, reduction of cytochrome P4502E1 mRNA levels and a massive increase in mRNA expression of heme oxygenase-1 and heat shock protein 70. Moreover, CCl 4 intoxication induced a severe decrease of mitochondrial respiratory chain complex IV activity, mitochondrial DNA depletion and damage as well as ultrastructural alterations. Whereas DDTC totally or partially prevented all these hepatic toxic events, both antioxidants protected only against liver lipid peroxidation and mitochondrial damage. Taken together, our results suggest that lipid peroxidation is primarily implicated in CCl 4 -induced early mitochondrial injury. However, lipid peroxidation-independent mechanisms seem to be involved in CCl 4 -induced early hepatocyte swelling and changes in expression of stress/defense-related genes. Antioxidant therapy may not be an efficient strategy to block early liver damage after CCl 4 intoxication.

Endoplasmic Reticulum Stress-induced Hepatocellular Death Pathways Mediate Liver Injury and Fibrosis via Stimulator of Interferon Genes

“…Moreover, the Knockaert et al (38) study similarly found CCl 4 -mediated necrosis at 24 h (Fig. 4K and 7F), further supporting our hypothesis that early and extensive pro-apoptotic signaling leads to necrosis, or secondary necrosis, which have overlapping components (39).…”

Carbon tetrachloride-induced hepatic and renal damages in rat: inhibitory effects of cacao polyphenol

“…35) As shown in Table 3, CPE was effective in preventing CCl 4 -induced CYP2E1 mRNA degradation, which is in agreement with the previous report showing that cacao polyphenol metabolites acted as potent inhibitors of CYP2E1 activity. 36) The inhibitory effects of CPE on CYP2E1 activity may provide an explanation for CPE antioxidant properties against CCl 4 -induced oxidative stress beyond its capacity to scavenge CCl 4 -induced radicals directly, although further work is required to establish the causal relationship between CPE and PCOOH, MDA, GPx, and CYP2E1 activity.…”

Suppressive Effect of Kampo Formula “Juzen-taiho-to” on Carbon Tetrachloride-Induced Hepatotoxicity in Mice

“…4,20) Moreover, CCl 4 is a prototypical lipid peroxidant that induces early lipid peroxidation in the liver. 8) As a marker of lipid peroxidation, MDA concentration was measured in all animal groups. CCl 4 treatment significantly increased MDA levels, whereas pretreatment with JTX eliminated CCl 4 -induced MDA upregulation (Fig.…”

“…In addition, associated protective mechanisms possibly act on each of the five steps. [7][8][9][10] The Japanese herbal medicine "Juzen-taiho-to" (JTX) is a Kampo medicinal prescription, and has been used historically in Japan for the treatment of cancers, rheumatoid arthritis, and atopic dermatitis. 11) JTX is consisting of ten medicinal herbs in the indicated amounts (g per day in human intake);…”