title: Effects of ciprofibrate and 2-[5-(4-chlorophenyl)pentyl]oxirane-2-carboxylate (POCA) on the distribution of carnitine and CoA and their acyl-esters and on enzyme activities in rats. Relation between hepatic carnitine concentration and carnitine acetyltransferase activity.
abstract: The effects of feeding the peroxisome proliferators ciprofibrate (a hypolipidaemic analogue of clofibrate) or POCA (2-[5-(4-chlorophenyl)pentyl]oxirane-2-carboxylate) (an inhibitor of CPT I) to rats for 5 days on the distribution of carnitine and acylcarnitine esters between liver, plasma and muscle and on hepatic CoA concentrations (free and acylated) and activities of carnitine acetyltransferase and acyl-CoA hydrolases were determined. Ciprofibrate and POCA increased hepatic [total CoA] by 2 and 2.5 times respectively, and [total carnitine] by 4.4 and 1.9 times respectively, but decreased plasma [carnitine] by 36-46%. POCA had no effect on either urinary excretion of acylcarnitine esters or [acylcarnitine] in skeletal muscle. By contrast, ciprofibrate decreased [acylcarnitine] and [total carnitine] in muscle. In liver, ciprofibrate increased the [carnitine]/[CoA] ratio and caused a larger increase in [acylcarnitine] (7-fold) than in [carnitine] (4-fold), thereby increasing the [short-chain acylcarnitine]/[carnitine] ratio. POCA did not affect the [carnitine]/[CoA] and the [short-chain acylcarnitine]/[carnitine] ratios, but it decreased the [long-chain acylcarnitine]/[carnitine] ratio. Ciprofibrate and POCA increased the activities of acyl-CoA hydrolases, and carnitine acetyltransferase activity was increased 28-fold and 6-fold by ciprofibrate and POCA respectively. In cultures of hepatocytes, ciprofibrate caused similar changes in enzyme activity to those observed in vivo, although [carnitine] decreased with time. The results suggest that: (1) the reactions catalysed by the short-chain carnitine acyltransferases, but not by the carnitine palmitoyltransferases, are near equilibrium in liver both before and after modification of metabolism by administration of ciprofibrate or POCA; (2) the increase in hepatic [carnitine] after ciprofibrate or POCA feeding can be explained by redistribution of carnitine between tissues; (3) the activity of carnitine acetyltransferase and [total carnitine] in liver are closely related.
authors.affiliation: Department of Child Health and Clinical Biochemistry, University of Newcastle upon Tyne, U.K.
authors.forename: A K
authors.initials: AK
authors.lastname: Bhuiyan
authors.forename: K
authors.initials: K
authors.lastname: Bartlett
authors.forename: H S
authors.initials: HS
authors.lastname: Sherratt
authors.forename: L
authors.initials: L
authors.lastname: Agius
mesh_terms: D000214:Acyl Coenzyme A / Q000378:metabolism; D000818:Animals; D002331:Carnitine / Q000031:analogs & derivatives / Q000378:metabolism*; D002332:Carnitine O-Acetyltransferase / Q000378:metabolism; D002478:Cells, Cultured; D002994:Clofibrate / Q000031:analogs & derivatives*; D002995:Clofibric Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D003065:Coenzyme A / Q000378:metabolism*; D004852:Epoxy Compounds / Q000494:pharmacology*; D004988:Ethers, Cyclic / Q000494:pharmacology*; D058607:Fibric Acids; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D000960:Hypolipidemic Agents / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D014018:Tissue Distribution
chemical_list: D000214:Acyl Coenzyme A; D004852:Epoxy Compounds; D004988:Ethers, Cyclic; D058607:Fibric Acids; D007004:Hypoglycemic Agents; D000960:Hypolipidemic Agents; D002995:Clofibric Acid; C033891:ethyl 2-(5-(4-chlorophenyl)pentyl)oxiran-2-carboxylate; D002332:Carnitine O-Acetyltransferase; C019304:ciprofibrate; D002994:Clofibrate; D002331:Carnitine; D003065:Coenzyme A