Studies on the mechanism of the inhibitory effects of erucylcarnitine in rat heart mitochondria.
1. The mechanism of the inhibitory effect of erucylcarnitine on palmityl-carnitine oxidation in rat heart mitochondria was studied. 2. Erucylcarnitine inhibited in the same time the oxidation of [U-14-C]-palmitylcarnitine and the total rate of oxygen uptake. Other acylcarnitines competed as well for the oxidation with radioactive palmitylcarnitine, but they were well oxidized themselves, so that the total oxygen uptake did not decrease. 3. The presence of erucylcarnitine did not change the distribution pattern of Krebs cycle intermediates derived from [U-minus 14 C] palmitylcarnitine except that succinate/malate ratio increased. 4. The presence of erucylcarnitine did not lead to the formation of any beta-oxidation cycle intermediates from [U-minus 14 C] palymitylcarnitine. The formation of beta-hydroxy-palmityl derivative when rotenon was included into the incubation medium, decreased in the presence of erucylcarnitine. 5. It is postulated, that the inhibited entrance of palmityl groups into the beta-oxidation cycle is due to the fact that erucylcarnitine and palmitylcarnitine behave as substrate-competitive inhibitors for long chain acyl-CoA dehydrogenase. 6. There was observed a latency of 1-2 min in the effect of erucylcarnitine on the palmitylcarnitine oxidation, which seems to correspond to the time required for the formation of high amounts of intramitochondrial erucyl-CoA. 7. Erucylcarnitine inhibited the total oxygen uptake with long, medium and short chain acylcarnitines, pyruvate and alpha-ketoglutarate as substrates, while the oxidation of succinate was not affected. 8. Sequestration of free CoA in the form of very slowly metabolized erucyl-CoA is proposed as the partial explanation of the observed inhibitory effects of erucylcarnitine on the oxidation of CoA-dependent substrates (alternatively to the inhibition at the level of acyl-CoA dehydrogenases in case of acylcarnitines).
D000818:Animals; D002331:Carnitine / Q000378:metabolism / Q000494:pharmacology*; D002952:Citric Acid Cycle / Q000187:drug effects; D003065:Coenzyme A / Q000378:metabolism; D004883:Erucic Acids / Q000494:pharmacology*; D005227:Fatty Acids / Q000378:metabolism / Q000494:pharmacology; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology*; D007700:Kinetics; D008053:Lipid Mobilization / Q000187:drug effects; D008931:Mitochondria, Muscle / Q000187:drug effects / Q000378:metabolism*; D009206:Myocardium; D010101:Oxygen Consumption / Q000187:drug effects; D010169:Palmitic Acids / Q000378:metabolism; D010944:Plants; D051381:Rats; D013329:Structure-Activity Relationship; D013997:Time Factors
D004883:Erucic Acids; D005227:Fatty Acids; D005231:Fatty Acids, Unsaturated; D010169:Palmitic Acids; D002331:Carnitine; D003065:Coenzyme A