Fatty acids, biliary bile acids, lipid peroxidation products and gallbladder carcinogenesis.

Secondary bile acids, by virtue of their lipophilic action, change the membrane composition of hepatocyte mitochondria, the inner membranes of which harbour the cytochrome P450 oxido-reductase system. The changes in the membrane fatty acid composition decreases the activity of the mitochondrial enzyme system, thereby making them incapable of handling free radicals generated during the normal process of energy production and detoxification. These free radicals in turn may attack membrane polyunsaturated fatty acids to initiate and propagate lipid peroxidation, leading to formation of aldehydic lipid peroxidation products. Notably among these is 4-hydroxynonenal, which has a high genotoxic and neoplastic potential. Disorders of gallbladder contractility further lead to accumulation of these toxic substances normally excreted in bile, and if retained for long time in the gallbladder they may induce gallbladder carcinogenesis.