We have determined the comparative activities of peroxisomal proliferators, ciprofibrate and clofibric acid on various hepatic parameters associated with endoplasmic reticulum, mitochondria and peroxisomes in primary cultures of rat hepatocytes. We have measured the activities of carnitine acetyltransferase and fatty acylCoA oxidase, and the amount of 60 and 80 kD polypeptides as biochemical markers of the peroxisomal function; laurate hydroxylase and cytochrome P-450 as markers of the endoplasmic reticulum; and carnitine palmitoyltransferase as a marker of mitochondria in primary cultures of hepatocytes. Ciprofibrate (0.01 to 0.3 mM) and clofibric acid (0.1 to 3 mM) produced similar changes in several components of cultured hepatocytes within 72 hr. Increases of protein (18 and 11%), carnitine palmitoyltransferase (23 and 97%), cytochrome P-450 (37 and 49%), carnitine acetyltransferase (484 and 614%), fatty acylCoA oxidase (529 and 931%) and laurate hydroxylase (624 and 671%) were obtained in hepatocytes after a 72-hr exposure to 0.1 mM ciprofibrate and 1.0 mM clofibric acid, respectively. In cultured hepatocytes, ciprofibrate was about 30-fold more active than clofibric acid for the stimulation of carnitine acetyltransferase, laurate hydroxylase and fatty acylCoA oxidase activities. Ciprofibrate was also more potent than clofibric acid as an inducer of the 60 and 80 kD proteins in hepatocytes. The maximal drug-induced increases in carnitine acetyltransferase activity were not additive, and the induction of carnitine acetyltransferase by ciprofibrate was blocked by addition (1 micrograms per ml) of cycloheximide or actinomycin D. Changes in protein and RNA synthesis preceded the drug-induced increases of carnitine acetyltransferase activity.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetyltransferases↗

PubMedDate not supplied

Biotransformation of D(-)-ephedrine and L(+)-ephedrine in the rabbit, in vivo and in vitro.

Investigations were carried out with radiolabeled D(-)-ephedrine and L(+)-ephedrine to establish whether differences exist in their metabolic fate in the rabbit, in vivo and in vitro. In liver microsomal preparations, a) D(-)-ephedrine was metabolized at a faster rate than L(+)-ephedrine, b) benzoic acid was formed from D(-)ephedrine at a rate about three times greater than from the L(+)-isomer, and c) the relative amounts of norephedrine and 1-phenyl-1,2-propranediol formed from both ephedrine isomers were nearly identical throughout the entire incubation period. In vivo, both ephedrine isomers were extensively metabolized and the majority of total radioactivity (71-91%) was excreted within 24 hr. A greater 14C-excretion rate was observed for L(+)-ephedrine. From an analysis of 0- to 24-hr urine, it was found that a) 47-50% of the urinary 14C was attributable to acidic metabolites (hippuric acid and benzoic acid) from L(+)- and D(-)-ephedrine, b) from 4 to 16% of the total 14C obtained with both isomers was accountable as 1-phenyl-1,2-propanediol, either free or as a glucuronide conjugate, c) no appreciable quantities of sulfate or glucuronide conjugates of p-hydroxylated metabolites of ephedrine or norephedrine was detectable, and d) small amounts (less than 4% of metabolites corresponding to unchanged ephedrine, norephedrine, or 1-hydroxy-1-phenyl-2-propanone were found in urine of animals given either isomer. These experiments indicate that the major pathway for the biotransformation of D(-)-ephedrine and L(+)-ephedrine involves N-demethylation and oxidative deamination of the side chain.

Animals↗