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.

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.