Interactions of inhibitors of carnitine palmitoyltransferase I and fibrates in cultured hepatocytes.
Culture of rat hepatocytes with etomoxir, an inhibitor of carnitine palmitoyltransferase I (CPT I), for 48 h, resulted in increased carnitine acetyltransferase (CAT) activity (74%), a marked decrease in CPT activity (82%) measured in detergent extracts, and increased activities of glucose-6-phosphate dehydrogenase (227%) and fructose-1,6-bisphosphatase (65%). Changes in CAT and CPT activities were not observed after 4 h culture with etomoxir. When hepatocytes were cultured with etomoxir and benzafibrate (a hypolipidaemic analogue of clofibrate) for 48 h, etomoxir prevented the 5-fold increase in CAT activity caused by bezafibrate, whereas bezafibrate suppressed the increase in glucose-6-phosphate dehydrogenase and fructose-bisphosphatase caused by etomoxir. However, bezafibrate did not prevent the suppression of CPT activity by etomoxir. Etomoxir inhibited palmitate beta-oxidation and ketogenesis after short-term (0-4 h) and long-term (48 h) exposure, but it caused accumulation of triacylglycerol in hepatocytes only after short-term exposure (0-4 h). These effects of etomoxir on fatty acid metabolism and suppression of CPT (after 48 h) were similar in periportal and perivenous hepatocytes, but the increases in CAT and glucose-6-phosphate dehydrogenase activities were higher in periportal than in perivenous cells. The effects of CPT I inhibitors on CAT activity and long-term suppression of CPT activity are probably mediated by independent mechanisms.
Department of Medicine, University of Newcastle upon Tyne, U.K.
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Gerondaes
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Alberti
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Agius
D000217:Acyltransferases / Q000037:antagonists & inhibitors*; D000818:Animals; D001629:Bezafibrate / Q000494:pharmacology*; D002334:Carnitine O-Palmitoyltransferase / Q000037:antagonists & inhibitors*; D002478:Cells, Cultured; D002994:Clofibrate / Q000031:analogs & derivatives*; D002995:Clofibric Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D004852:Epoxy Compounds / Q000494:pharmacology*; D004988:Ethers, Cyclic / Q000494:pharmacology*; D005227:Fatty Acids / Q000378:metabolism; D058607:Fibric Acids; D007527:Isoenzymes / Q000037:antagonists & inhibitors*; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D013997:Time Factors; D014280:Triglycerides / Q000378:metabolism
D004852:Epoxy Compounds; D004988:Ethers, Cyclic; D005227:Fatty Acids; D058607:Fibric Acids; D007527:Isoenzymes; D014280:Triglycerides; C052021:2-(6-(4-chlorophenoxy)hexyl)oxirane-2-carboxylic acid; D002995:Clofibric Acid; C035111:B 807-27; D000217:Acyltransferases; D002334:Carnitine O-Palmitoyltransferase; C019304:ciprofibrate; D002994:Clofibrate; D001629:Bezafibrate