Biomaterial Database

Fenofibrate: metabolism and species differences for peroxisome proliferation in cultured hepatocytes. 1995

M C Cornu-Chagnon, and H Dupont, and A Edgar

Laboratories Fournier, Centre de Recherches de Daix, Fontaine-les-Dijon, France.

The hypolipidemic agent fenofibrate, which is a peroxisome proliferator in some rodents in vivo, was studied in cultured hepatocytes for its metabolism and effects on enzymatic induction related to peroxisome proliferation so as to lead to a better understanding of the mechanisms involved in peroxisome proliferation. [14C]-Fenofibrate was completely metabolized within 24 hr by primary cultures of rat hepatocytes and the metabolic pattern corresponded to that found in vivo. The main products were fenofibric acid and its glucuronidated form. Carbonyl reduction of fenofibric acid also occurred. The metabolic pattern of [14C]fenofibric acid was nearly the same as that of fenofibrate. Fenofibrate, fenofibric acid, and its reduced metabolite all induced peroxisomal (cyanide-insensitive) palmitoyl-CoA oxidation activity (PCOA) in rat hepatocytes, whereas derivatives lacking the carboxyl group were nearly inactive. The known species differences with respect to sensitivity to peroxisome proliferators in vivo was mirrored in cultured cells because fenofibric acid did not induce peroxisomal PCOA in primary culture of guinea pig hepatocytes nor in the human hepatoma cell line HepG2. The mechanistic association between the induction of CYP4A1-catalyzed lauric acid omega-hydroxylase (LAH) activity and peroxisomal PCOA induction was investigated. Fenofibric acid concomitantly induced LAH activity and peroxisomal PCOA in rat hepatocytes. Specific inhibition of LAH activity (-52%) by 10-undecynoic acid partially prevented induction of peroxisomal PCOA (-32%). The putative role of dicarboxylic acids, the oxidation product of omega-hydroxymonocarboxylic acids, in PCOA induction was further substantiated by the observed induction of peroxisomal PCOA by 1-12-dodecanedioic acid. We conclude that (1) fenofibric acid is the possible proximate peroxisome proliferator of fenofibrate in rat hepatocytes, (2) cultured hepatocytes reflect in vivo sensitivity to fenofibrate with respect to peroxisome proliferation, and (3) there is some evidence that the catalytic activity of the CYP4A1 enzyme mediates, at least in part, peroxisomal PCOA induction.

UI	MeSH Term	Description	Entries
D008099	Liver	A large lobed glandular organ in the abdomen of vertebrates that is responsible for detoxification, metabolism, synthesis and storage of various substances.	Livers
D008297	Male		Males
D008830	Microbodies	Electron-dense cytoplasmic particles bounded by a single membrane, such as PEROXISOMES; GLYOXYSOMES; and glycosomes.	Glycosomes,Glycosome,Microbody
D010171	Palmitoyl Coenzyme A	A fatty acid coenzyme derivative which plays a key role in fatty acid oxidation and biosynthesis.	Palmitoyl CoA,Hexadecanoyl CoA,Palmityl CoA,CoA, Hexadecanoyl,CoA, Palmitoyl,CoA, Palmityl,Coenzyme A, Palmitoyl
D011345	Fenofibrate	An antilipemic agent which reduces both CHOLESTEROL and TRIGLYCERIDES in the blood.	Procetofen,Antara Micronized Procetofen,Apo-Feno-Micro,Apo-Fenofibrate,CiL,Controlip,Fenobeta,Fenofanton,Fenofibrat AL,Fenofibrat AZU,Fenofibrat AbZ,Fenofibrat FPh,Fenofibrat Heumann,Fenofibrat Hexal,Fenofibrat Stada,Fenofibrat-ratiopharm,Fénofibrate Debat,Fénofibrate MSD,Gen-Fenofibrate,LF-178,Lipanthyl,Lipantil,Liparison,Lipidil,Lipidil-Ter,Livesan,Lofibra,MTW-Fenofibrat,Normalip,Novo-Fenofibrate,Nu-Fenofibrate,PMS-Fenofibrate Micro,Phenofibrate,Procetofene,Secalip,Supralip,Tricor,durafenat,fenofibrat von ct,AZU, Fenofibrat,Apo Feno Micro,Apo Fenofibrate,Debat, Fénofibrate,Fenofibrat ratiopharm,Gen Fenofibrate,Heumann, Fenofibrat,Hexal, Fenofibrat,LF 178,LF178,Lipidil Ter,MTW Fenofibrat,Micronized Procetofen, Antara,Novo Fenofibrate,Nu Fenofibrate,PMS Fenofibrate Micro,Procetofen, Antara Micronized,Stada, Fenofibrat
D002478	Cells, Cultured	Cells propagated in vitro in special media conducive to their growth. Cultured cells are used to study developmental, morphologic, metabolic, physiologic, and genetic processes, among others.	Cultured Cells,Cell, Cultured,Cultured Cell
D002995	Clofibric Acid	An antilipemic agent that is the biologically active metabolite of CLOFIBRATE.	Clofibrinic Acid,2-(4-Chlorophenoxy)-2-methylpropionic Acid,NSC-1149,p-Chlorophenoxyisobutyrate,p-Chlorophenoxyisobutyric Acid,NSC 1149,NSC1149
D003577	Cytochrome P-450 Enzyme System	A superfamily of hundreds of closely related HEMEPROTEINS found throughout the phylogenetic spectrum, from animals, plants, fungi, to bacteria. They include numerous complex monooxygenases (MIXED FUNCTION OXYGENASES). In animals, these P-450 enzymes serve two major functions: (1) biosynthesis of steroids, fatty acids, and bile acids; (2) metabolism of endogenous and a wide variety of exogenous substrates, such as toxins and drugs (BIOTRANSFORMATION). They are classified, according to their sequence similarities rather than functions, into CYP gene families (>40% homology) and subfamilies (>59% homology). For example, enzymes from the CYP1, CYP2, and CYP3 gene families are responsible for most drug metabolism.	Cytochrome P-450,Cytochrome P-450 Enzyme,Cytochrome P-450-Dependent Monooxygenase,P-450 Enzyme,P450 Enzyme,CYP450 Family,CYP450 Superfamily,Cytochrome P-450 Enzymes,Cytochrome P-450 Families,Cytochrome P-450 Monooxygenase,Cytochrome P-450 Oxygenase,Cytochrome P-450 Superfamily,Cytochrome P450,Cytochrome P450 Superfamily,Cytochrome p450 Families,P-450 Enzymes,P450 Enzymes,Cytochrome P 450,Cytochrome P 450 Dependent Monooxygenase,Cytochrome P 450 Enzyme,Cytochrome P 450 Enzyme System,Cytochrome P 450 Enzymes,Cytochrome P 450 Families,Cytochrome P 450 Monooxygenase,Cytochrome P 450 Oxygenase,Cytochrome P 450 Superfamily,Enzyme, Cytochrome P-450,Enzyme, P-450,Enzyme, P450,Enzymes, Cytochrome P-450,Enzymes, P-450,Enzymes, P450,Monooxygenase, Cytochrome P-450,Monooxygenase, Cytochrome P-450-Dependent,P 450 Enzyme,P 450 Enzymes,P-450 Enzyme, Cytochrome,P-450 Enzymes, Cytochrome,Superfamily, CYP450,Superfamily, Cytochrome P-450,Superfamily, Cytochrome P450
D004305	Dose-Response Relationship, Drug	The relationship between the dose of an administered drug and the response of the organism to the drug.	Dose Response Relationship, Drug,Dose-Response Relationships, Drug,Drug Dose-Response Relationship,Drug Dose-Response Relationships,Relationship, Drug Dose-Response,Relationships, Drug Dose-Response
D004790	Enzyme Induction	An increase in the rate of synthesis of an enzyme due to the presence of an inducer which acts to derepress the gene responsible for enzyme synthesis.	Induction, Enzyme