ON THE EFFECTS OF THIA FATTY-ACID ANALOGS ON HYDROLASES INVOLVED IN THE DEGRADATION OF METABOLIZABLE AND NONMETABOLIZABLE ACYL-COA ESTERS

1. We investigated the nature and roles of various xenobiotic acyl-CoA hydrolases in liver subcellular fractions from rat treated with sulph ur-substituted (thia) fatty acids. To contribute to our understanding of factors influencing enzymes involved in the degradation of activate d fatty acids, the effects on these activities of the oppositely actin g thia fatty acid analogues, the peroxisome proliferating 3-thia fatty acids (tetradecylthioacetic acid and 3-dithiacarboxylic acid), which are blocked for beta-oxidation, and a non-peroxisome-proliferating 4-t hia fatty acid (tetradecylthiopropionic acid), which undergoes one cyc le of beta-oxidation, were studied. 2. The hepatic subcellular distrib utions of palmitoyl-CoA, tetradecylthioacetyl-CoA and tetradecylthiopr opionyl-CoA hydrolase activities were similar to each other in the con trol and 3-thia fatty acid-treated rat. In control animals, most of th ese hydrolases were located in the microsomal fraction, but after trea tment with the 3-thia fatty acids, the specific activities of the mito chondrial, peroxisomal, and cytosolic palmitoyl-CoA, tetradecylthioace tyl-CoA, and tetradecylthiopropionyl-CoA hydrolase activities were sig nificantly increased. This increase in activity was seen mostly for th e enzymes using tetradecylthiopropionyl-CoA and tetradecylthioacetyl-C oA as substrates. The increased mitochondrial activities for these two substrates were seen already after 1 day of treatment, whereas the pe roxisomal activities increased after 3 days. No stimulation was seen a fter treatment with the 4-thia fatty acid analogue, tetradecylthioprop ionic acid, but a decrease in peroxisomal hydrolase activities for all three substrates was observed. 3. The cellular distributions of clofi broyl-CoA, POCA-CoA, and sebacoyl-CoA hydrolase activities were differ ent from those of the 'long-chain acyl-CoA' hydrolases mentioned above both in the normal and 3-thia fatty acid treated rat. This group of h ydrolases was found in the mitochondrial, peroxisomal, and cytosolic f ractions. 3-Thia fatty acid treatment increased the activities of clof ibroyl-CoA and sebacoyl-CoA hydrolases in all three fractions. Clofibr oyl-CoA and sebacoyl-CoA hydrolase activities were increased after 1 d ay of treatment. Only the cytosolic POCA-CoA hydrolase was stimulated after 3-thia fatty acid treatment after only 1 day of treatment, where as treatment with the 4-thia fatty acid led to an increase of enzyme a ctivity in the mitochondrial and peroxisomal fractions. 4. Based on th e subcellular distributions and specific activities, we suggest that s everal enzymes exist which may act as regulators of intracellular acyl -CoA levels.