Carbon tetrachloride toxicity as a model for studying free-radical mediated liver injury [and discussion]

A single dose of CCl4 when administered to a rat produces centrilobular necrosis and fatty degeneration of the liver. These hepatotoxic effects of CCl4 are dependent upon its metabolic activation in the liver endoplasmic reticulum to reactive intermediates, including the trichloromethyl free radical. Positive identification of the formation of this free radical in vivo, in isolated liver cells and in microsomal suspensions in vitro has been achieved by e.s.r. spin-trapping techniques. The trichloromethyl radical has been found to be relatively unreactive in comparison with the secondarily derived peroxy radical CCl3O2., although each free radical species contributes significantly to the biological disturbances that occur. Major early perturbations produced to liver endoplasmic reticulum by exposure in vivo or in vitro to CCl4 include covalent binding and lipid peroxidation; studies of these processes occurring during CCl4 intoxication have uncovered a number of concepts of general relevance to free-radical mediated tissue injury. Lipid peroxidation produces a variety of substances that have high biological activities, including effects on cell division; many liver tumours have a much reduced rate of lipid peroxidation compared with normal liver. A discussion of this rather general feature of liver tumours is given in relation to the liver cell division that follows partial hepatectomy.Peer reviewed: YesNRC publication: Ye

Lipid antioxidants and products of lipid peroxidation as potential tumour protective agents

Peer reviewed: YesNRC publication: Ye

Lipid peroxidation and lipid antioxidants in normal and tumor cells

Peer reviewed: YesNRC publication: Ye

Application of deuterated a-tocopherols to the biokinetics and bioavailability of vitamin e

\u3b1Tocopherol, a superior chain-breaking, peroxyl radical-trapping antioxidant and the most active component of vitamin E, is elevated in liver tumor cells, contributing to their greater resistance towards lipid peroxidation compared to cells from normal tissues. Also, in regenerating rat liver the level of vitamin E has been found to fluctuate in phase with the rate of cell division. In order to study the biokinetcis and mechanisms of the distribution of vitamin E in organs and within tissues of animals, deuterated forms of \u3b1tocopherol have been synthesized and their uptake into blood and tissues has been measured by gas chromatography-mass spectrometry. Measurement of the competitive uptake from a mixture of the RRR-and SRR-\u3b1tocopherol stereoisomers labelled with different amounts of deuterium shows that the liver exerts a strong preference for secretion of the natural (RRR) stereoisomer into the plasma. It is suggested that a tocopherol-binding protein plays a key role in this process. \ua9 1990 Informa UK Ltd All rights reserved: reproduction in whole or part not permitted.Peer reviewed: YesNRC publication: Ye

Studies on lipid peroxidation in normal and tumour tissues. The Yoshida rat liver tumour

Reduced rates of lipid peroxidation have been observed in Yoshida hepatoma cells and microsomes when compared with appropriate control tissue (normal rat liver) under the same pro-oxidant conditions. The pro-oxidant conditions used were incubation with NADPH + ADP + iron or ascorbate + iron or exposure to \u3b3-irradiation. As previously shown with the Novikoff hepatoma, the relative concentrations of \u3b1-tocopherol and polyunsaturated fatty acids are important in conferring resistance to lipid peroxidation in the Yoshida hepatoma. Furthermore, NADPH-cytochrome P-450 electron transport chain, which are involved in the initiation and propagation of certain types of lipid peroxidation, are found at very much reduced levels in the Yoshida hepatoma. The relative importance of these aberrations are discussed.Peer reviewed: YesNRC publication: Ye

Studies on lipid peroxidation in normal and tumour tissues. The Novikoff rat liver tumour

A study has been made of the factors that contribute to the decreased rates of lipid peroxidation under different pro-oxidant conditions in intact Novikoff tumour cells, and in microsomal suspensions prepared from Novikoff tumour cells, compared with isolated normal rat hepatocytes and microsomal suspensions prepared from normal rat liver. The pro-oxidant conditions were the addition of either NADPH, NADPH + ADP + iron, NADPH + CCl4 or ascorbate + iron to the experimental systems used, or exposure to \u3b3-radiation. Contributory factors to the lower rates of lipid peroxidation observed include: (a) a significant decrease in the polyunsaturated fatty acid content of Novikoff cells or Novikoff microsomes; the decreases are especially marked for the C(20:4) and C(22:6) fatty acids; (b) a very marked reduction in NADPH-cytochrome c reductase; and (c) no detectable content of cytochrome P-450. Another, and in our opinion critical, contribution to the diminished rate of lipid peroxidation in the tumour material is the substantial increase in \u3b1-tocopherol relative both to total lipid and to methylene-interrupted double bonds in fatty acids. Moreover, the \u3b1-tocopherol is the major contributor to lipid-soluble chain-breaking antioxidant in lipid extracts of normal liver and of Novikoff tumour material.Peer reviewed: YesNRC publication: Ye