Biological significance of compartmentation of hepatic ethanol oxidation

Intact cell preparations, isolated from the livers of fasted rats and treated with rotenone or antimycin A, retain a limited ability to oxidize long chain fatty acids but not short chain species or other usual substrates. Cells prepared from livers of animals treated with clofibrate to induce peroxisomal proliferation have even greater long chain fatty acid oxidizing capacity in the presence of these inhibitors. We infer that the peroxisomes of intact cells are capable of catabolizing long chain fatty acids by a superoxide-generating pathway. In normal cells or those from clofibrate-treated rats, reducing equivalents generated within peroxisomes compete with those originating in the cytosol for mitochondrial disposition. Because of this, peroxisomal fatty acid metabolism inhibits ethanol oxidation. Peroxisomal oxidations appear to be coupled to conversation of free energy and mitochondrial-peroxisomal relationships are regulated by interaction of free-energy transducing processes. Hence, uncoupling agents release the inhibition of ethanol oxidation induced by long chain fatty acid. When mitochondrial metabolism is impaired, reducing equivalents may flow from mitochondria to peroxisomes for reaction with O2. Thus, there exists a two-way interaction between these organelles. The biological and pathological implications of these relationships for ethanol oxidation and overall energy metabolism are discussed.