Biochemical changes in carbon tetrachloride fatty liver: separation of fatty changes from mitochondrial degeneration.

In 1954 Christie and Judah (3) in a study of the mechanism of action of carbon tetrachloride advanced the view that the primary locus of action of this hepatotoxin was the membranes of the liver mitochondria. Dianzani (4-6) showed that after carbon tetrachloride or phosphorus poisoning or after a choline deficient diet, there was evidence for uncoupling of oxidative phosphorylation, loss of mitochondrial pyridine nucleotides, and lowering of the liver content of adenosine triphosphate. Dianzani suggested that the key lesion in toxic and nutritional fatty liver involved a loss of mitochondrial function, leading primarily to a lowering of the supply of adenosine triphosphate, and secondarily to a failure of the fatty acid activation reaction, thus accounting for the increase in liver fat on the basis of a failure of fat oxidation. The central question addressed by the experiments reported in this communication is the following. Can the characteristic increase in liver fat occurring in carbon tetrachloride fatty liver be accounted for by a primary degeneration of the liver mitochondria? The theoretical position taken on this question was a simple one. If the increase in fat is due ultimately to loss of those phases of cellular metabolism sustained by the mitochondria, then clear cut evidence of the failure of the relevant mitochondrial functions should appear before the increase in fat. The experimental approach was therefore simplified to a correlation in time of the first appearance of mitochondrial degeneration with the time of onset of the fatty changes. Although confirming some of the previous findings, the main hypothesis, viz. that increased liver fat depends on a primary loss of mitochondrial function, has not been confirmed. Supporting experimental data on the effects in vitro of carbon tetrachloride and other fat solvents on mitochondrial and microsomal enzyme systems are included.