Induction clofibrate

With the clofibrate type of inducer, other changes are also apparent. Thus, there is a proliferation in the number of peroxisomes (an intracellular organelle) as well as induction of a particular form of cytochrome P-450 involved in fatty acid metabolism. A number of other enzymes associated with the role of this organelle in fatty acid metabolism are also increased, such as carnitine acyltransferase and catalase. This phenomenon is discussed in more detail in chapter 6. 

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.

As well as cytochrome P-450, other enzymes are induced by peroxisome proliferators such as clofibrate. Thus enzymes involved in the 3-oxidation of fatty acids are increased and other structural proteins are also increased (see chap. 7). This is, therefore, another example of a pleiotropic effect, similar to the induction via the AhR discussed above. 

In those species, which are responsive (i.e., have a functioning receptor) such as the rat, treatment with drugs, which interact with the PPARa receptor such as clofibrate, will cause a number of effects, such as induction of a number of enzymes, increased cell growth and turnover, and liver tumors in almost all the animals as a direct result of interaction with the receptor and changes in gene transcription. This will be discussed in more detail in chapter 7. 

Fibrates (such as clofibrate) are hypolipidemic drugs. They cause a number of biological and biochemical effects, including enzyme induction, peroxisomal proliferation, liver hypertrophy and hyperplasia, and liver cancer. The mechanism is believed to be mediated through the PPARa receptor. Animals lacking this receptor do not show these effects. 

Gill SS, Kaur S. 1987. Hepatic epoxide hydrolase activities and their induction by clofibrate and dicthylhcxylphthalatc in various strains ofmice. Biochem Pharmacol 36 4221-4227. 

Sharma R, Lake BG, Gibson GG. 1988. Co-induction of microsomal cytochrome P-452 and the peroxisomal fatty acid -oxidation pathway in therat by clofibrate and di-(2-ethylhexyl)phthalate. 

Moffit JS, Aleksunes LM, Maher JM, et al. Induction of hepatic transporters multidrug resistance-associated proteins (Mrp) 3 and 4 by clofibrate is regulated by peroxisome proliferator-activated receptor alpha. J Pharmacol Exp Ther 2006 317 537-545. 

Houin G, Thlement JP. Clofibrate and enzymatic induction in man. Int J Clin Pharmacol Biopharm 1978 16(4) 150-4. 

Clofibrate at a concentration of 0.5 mmol in culture medium maintained the cytochrome P-450 content of rat hepatocytes for up to 96 h. This effect was associated with a marked induction of lauric acid hydroxylation whereas little effect was observed on the metabolism of three other cytochrome p450 dependent mixed function oxidase substrates. 

Currently, over 100 compounds have been identified as PPs. The literature indicates that induction of peroxisome proliferation is not limited to exogenous chemicals. A number of endogenous substances, such as the steroid hormones, thyroid hormones, mor-phogenes, and fatty acids, are also involved in peroxisome proliferation. Peroxisome proliferation in hepatic parenchymal cells of rats and mice following the administration of clofibrate has been reported by numerous investigators. Compounds that are structurally unrelated to clofibrate, such as acetaminophen and Wy-14,643, can also cause peroxisome proliferation (Table 1). The industrial solvent trichloroethylene, the industrial plasticizers dill-ethyl hexyl) phthalate (DEHP) and di(2-ethyl hexyl) adipate (DEHA), have also been found to be hepatic peroxisome proliferators. 

Figure 4.4 Species differences in clofibric acid-induced expression of CYP4A-specific activity (lauric acid 12-hydroxylation) represented as fold induction over control levels.

With the clofibrate type of inducer other changes are also apparent. Thus, there is a proliferation in the number of peroxisomes (an intracellular organelle), as well as induction of a particular form of cytochrome P-450 involved in fatty acid metabolism. A number of other enzymes associated with the role of this organelle in fatty acid metabolism are also increased, such as carnitine acyltransferase and catalase. This phenomenon is discussed in more detail in Chapter 6. The onset of the inductive response is in the order of a few hours (3-6 h after polycyclic hydrocarbons, 8-12 h after barbiturates), is maximal after 3-5 days with barbiturates (24-48 h with polycyclic hydrocarbons) and lasts for at least 5 days (somewhat longer with polycyclic hydrocarbon induction). The magnitude of the inductive effect may depend on the size and duration of dosing with the inducer, and will also be influenced by the sex, species, strain of animal and the tissue exposed. 

The ABC transporters Mrp3, Mrp4, and Bcrp are induced by clofibrate in the livers of mice [105, 145] and it was shown that induction by clofibrate depends on PPARa [145],... 

Houin G, Tillement J-P. Clofibrate and en matic induction in man. IntJ Clin Pharmacol Ther Toxicol( 97Z) 16,15(M. 

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