CARBON TETRACHLORIDE HEPATOTOXICITY

During the past 20 years, study of the fatty liver induced by carbon tetrachloride has passed through 2 periods of revolutionary change, and at the present time a third revolutionary change is taking place. The dominant notion guiding most of the thinking before 1948 was that toxic and nutritional fatty liver disease could be understood in terms of failure in transport of fatty acids as phospholipids. As quantitative analyses of whole body phospholipid and neutral lipid metabolism became available through application of radioisotope technology, it became possible by 1953 to conclude that fatty acids were not transported in the plasma as phospholipids. For the next 6 years work in this field was dominated by the mitochondrial hypothesis. Carbon tetrachloride was thought to damage the liver cell mitochondria. It was suggested that lipid accumulation was due to a failure of normal pathways of lipid oxidation, and that death of the liver cells resulted from interruption in energy-transducing mechanisms. By 1959 this hypothesis also proved untenable since accumulation of triglycerides and degeneration of the hepatocellular endoplasmic reticulum preceeded mitochondrial degeneration by many hours. The major contribution of the work of this period was the introduction into the study of experimental hepatic toxicology of methods of biochemical cytology. A second revolutionary change took place in 1960. It became evident that carbon tetrachloride poisoning leads rapidly to cessation of movement of large quantities of triglycerides from the liver to the plasma. The blockade of hepatic triglyceride secretion by carbon tetrachloride accounts for the characteristic fatty liver. Earlier studies of rates of replacement of the different moieties of the plasma lipoproteins had demonstrated that low-density lipoprotein triglycerides were replaced much faster than the protein moiety. This work, as well as more recent studies combining use of the isolated, perfused liver with methods for separation of plasma protein and lipoprotein fractions, has made possible a most important new insight into the nature of hepatic triglyceride secretion. The latter can best be understood as a dual mechanism. One part of the mechanism involves hepatic biosynthesis of the various moieties of plasma low-density lipoproteins, coupling of these to form definitive lipoprotein molecules, and their extrusion to the plasma compartment. An auxiliary mechanism provides for re-entry into the system of triglyceride-free lipoprotein apoprotein. Movement of triglycerides from liver to plasma depends largely on the continuous functioning of the second, or auxiliary arm of the cycle. The knowledge that hepatic triglyceride secretion involves a dual mechanism has provided a powerful new guide for the analysis of mechanisms underlying fatty liver disease. In the case of carbon tetrachloride poisoning, the rapid onset of liver triglyceride accumulation most probably results mainly from cessation in function of the auxiliary coupling phase of hepatic triglyceride secretion, and less significantly from a breakdown in hepatic protein synthesis. During this period, ca . 1960 to 1965, highly provocative experimental findings led to an attempt to rationalize the hepatocellular necrosis and the triglyceride accumulation of carbon tetrachloride poisoning in terms of massive discharge of the sympathetic nervous system. The main evidence regarding the pathogenesis of hepatocellular necrosis was based on the observation that rats whose spinal cord had been divided were remarkably immune to the toxic agent. A review of the evidence does not support the contention that hepatocellular necrosis is a consequence of catecholamine discharge. The catecholamine hypothesis suggested that hepatic lipid accumulation is due to an oversupply of fatty acids mobilized from peripheral adipose tissue depots. Activation of the hypophyseal-adrenocortical axis has also been invoked in support of the peripheral oversupply hypothesis. A central requirement of this hypothesis must be that if oversupply of fatty acids is to be invoked as a significant factor in the pathogenesis of fatty liver, then the oversupply must be of sufficient magnitude and duration to account for the time course of the hepatic lipid accumulation. From this point of view the evidence offered in support of the peripheral oversupply hypothesis is not convincing. In particular, for carbon tetrachloride poisoning, at a time when liver triglycerides are increasing rapidly, there is no increase in flux of fatty acids through the plasma compartment. The most recent work in this field has inaugurated a third revolution in the study of carbon tetrachloride hepatotoxicity. Its essential feature is the recognition that carbon tetrachloride toxicity depends on cleavage of the carbon-tochlorine bond. At the same time, the long-held view that the toxic action of carbon tetrachloride resided in its effectiveness as a lipid solvent has finally been discarded. An important link has been established between the metabolism of carbon tetrachloride and the peroxidative decomposition of cytoplasmic membrane structural lipids. Sufficient data are not yet available to decide whether the latter effect is a major or minor consequence of the metabolism of carbon tetrachloride. The important point is that study of this problem has reached the organic chemical level of organization. This augurs well for the immediate future, which should witness further interesting new developments in the study of haloalkane toxicity.