Characterization of the hepatic responses to the short-term administration of ciprofibrate in several rat strain. Co-induction of microsomal cytochrome P-450 IVA1 and peroxisome proliferation.
The influence of ciprofibrate, a potent oxyisobutyrate derivative, on several hepatic enzyme parameters was studied in five rat strains following a 14-day treatment period. Ciprofibrate-dependent hepatomegaly was observed at two dose levels (2 and 20 mg/kg) in all rat strains examined. A 10- to 15-fold induction in the 12-hydroxylation of lauric acid with a less marked 1.5- to 5-fold induction of 11-hydroxylation was observed in treated animals. This dose-dependent increase in fatty acid hydroxylase activity was associated with a maximal 10-fold increase in the specific content of cytochrome P-450 IVA1 isoenzyme apoprotein, as assessed immunochemically using an ELISA technique. The activities of the cytochrome P-450 I (IA1 and IA2) and II (IIB1 and IIB2) families, as measured by ethoxyresorufin-O-deethylase and benzphetamine-N-demethylase activities respectively, were decreased on treatment. In the mitochondria, monoamine oxidase activity was significantly decreased at the higher dose level whereas alpha-glycerophosphate dehydrogenase activity was elevated. Total carnitine acetyltransferase activity (mitochondrial and peroxisomal) and peroxisomal beta-oxidation were markedly increased at both dose levels in all strains examined. Cytosolic glutathione peroxidase activity, measured using both t-butylhydroperoxide and hydrogen peroxide as substrates, was decreased on treatment to approximately 50% of the control value. In treated animals, a marked increase in mRNA levels coding for cytochrome P-450 IVA1 and the peroxisomal bifunctional protein of the fatty acid beta-oxidation spiral was observed. However, mRNA levels coding for glutathione peroxidase appeared unchanged following ciprofibrate administration, in contrast to the above-noted decrease of glutathione peroxidase enzyme activity. Taken collectively, our results have further substantiated a close association between the induction of microsomal cytochrome P-450 IVA1, peroxisomal beta-oxidation and total carnitine acetyltransferase activity in rat liver, and have performed a conceptual basis for the rationalization of the chronic toxicity of peroxisome proliferators in this species.
Makowska
J M
JM
University of Surrey, Department of Biochemistry, Molecular Toxicology Group, Guildford, U.K.
Anders
C
C
Goldfarb
P S
PS
Bonner
F
F
Gibson
G G
GG
D000284:Administration, Oral; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002994:Clofibrate / Q000031:analogs & derivatives*; D002995:Clofibric Acid / Q000031:analogs & derivatives* / Q000633:toxicity; D019363:Cytochrome P-450 CYP1A1; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D058607:Fibric Acids; D005979:Glutathione Peroxidase / Q000378:metabolism; D000960:Hypolipidemic Agents / Q000633:toxicity*; D008297:Male; D008830:Microbodies / Q000187:drug effects / Q000201:enzymology; D008862:Microsomes, Liver / Q000187:drug effects* / Q000201:enzymology; D009929:Organ Size / Q000187:drug effects; D010088:Oxidoreductases / Q000378:metabolism; D010089:Oxidoreductases, N-Demethylating / Q000378:metabolism; D051381:Rats; D011911:Rats, Gunn; D011916:Rats, Inbred F344; D011919:Rats, Inbred Strains; D013045:Species Specificity
D058607:Fibric Acids; D000960:Hypolipidemic Agents; D002995:Clofibric Acid; D003577:Cytochrome P-450 Enzyme System; D010088:Oxidoreductases; D005979:Glutathione Peroxidase; D019363:Cytochrome P-450 CYP1A1; C019781:benzphetamine N-demethylase; D010089:Oxidoreductases, N-Demethylating; C019304:ciprofibrate; D002994:Clofibrate