Clofibrate enzyme activity

Lake, B.G., Kozlen, S.L., Evans, J.G., Gray, T.J.B., Young, P.J. and Gangolli, S.D. (1987). Effect of prolonged administration of clofibric acid and di-(2-ethylhexyl)phthalate on hepatic enzyme activities and lipid peroxidation in the rat. Toxicology 44, 213-228. 

Figure 5.36 Mechanism of the receptor-mediated induction of CYP4A by a chemical such as the drug clofibrate. The inducer-receptor (PPAR) complex enters the nucleus, binds with RXR, and the complex binds to the receptor response elements in the CYP gene. This induces the production of CYP4A mRNA, which leads to the production of CYP4A protein and functional enzyme. Alternatively, the drug may perturb lipid metabolism leading to increases in a lipid(s), which will bind to the receptor and cause the same response. Abbreviations PPAR, peroxisome proliterator-activated receptor RXR, retinoid X receptor.

With the hypolipidemic drug-inducible cytochromes P-450 (CYP4A), there is transcriptional activation within 1 hour of administration of clofibrate. The levels of CYP4A1 are very low in the liver and kidney, but are markedly increased by the inducers. As well as cytochromes P-450, a number of other enzymes involved in peroxisomal p-oxidation reactions are also induced. 

Disposition in the Body. Readily and almost completely absorbed after oral administration. Rapidly hydrolysed by serum enzymes to clofibric acid, 2-(4-chlorophenoxy)-2-methylpropionic acid (active), which is conjugated with glucuronic acid. About 50 to 85% of a dose is excreted in the urine in 48 hours mostly as conjugated clofibric acid. 

Rifampin induces the activity of the hepatic microsomal enzyme, metabolizing numerous drugs including acetaminophen, anticoagulants, barbiturates, benzodiazepines, beta-blockers, chloramphenicol, clofibrate, contraceptives, corticosteroids, cyclosporine, digitoxin, disopyramide, estrogens, hydantoins, methadone, mexiletine, quinidine, sulfones, sul-fonylureas, theophyllines, tocainide, and verapamil. The plasma levels and effectiveness of these agents may be decreased. 

It is known that both the metabolism and the biological effects of 2-APA drugs can be modulated by other xenobiotics that influence the pool of free CoA or the activity of the CoA-dependent enzymes. Clofibrate and possibly other clofibric acid derivatives can increase the expression of long-chain acyl-CoA synthase and increase ibuprofen incorporation and tissue distribution into hybrid lipids in rats and humans [27,56-59]. The addition of valproic acid and pivalic acid, a metabolite of pivampicillin, to suspensions of isolated rat hepatocytes can also interfere with CoA pools and inhibit the formation of ibuprofenoyl-CoA reaction [60,61]. 

Investigation of the 3-hydroxyacyl-CoA dehydrogenase activities in purified rat liver peroxisomes, using the 3-hydroxyacyl-CoAs of straight chain fatty acids, of 2-methyl-branched chain fatty acids and of trihydroxycoprostanic acid as substrates, revealed initially 5 different enzymes (named I to V)." Enzyme IV was a monomeric 78 kD protein, possessed crotonase activity, was induced by clofibrate, and was identified as the inducible multifunctional protein. Interestingly, enzyme III, a monomeric 80 kD protein, also hydrated crotonyl-CoA. In contrast to enzyme IV, enzyme III was not induced by clofibrate." This was the first indication, pubhshed in 1994, that peroxisomes contained a second multifunctional protein. It was named multifunctional protein 2 (MFP-2) (the inducible, firstly isolated protein is referred to as MFP-1). Based on its substrate spectrum, the newly identified multifunctional protein was postulated to be involved in bile acid formation. ... 

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