Liver clofibrate effects

The viewpoint that the clofibrate effect is entirely through an enhanced peroxisomal p-oxidation has been challenged by Pande and Parvin (1980). These authors point out that the hypotriglyceridemic effect of clofibrate is seen equally in male and female rats although the peroxisomal proliferation is more pronounced in the livers of male rats (Svoboda et aL, 1967). Instead, the authors suggest that, since clofibrate triples the carnitine content of the liver, its effect may be due to enhanced, carnitine dependent, mitochondrial oxidation of fatty acids. 

Giometti CS et al. A comparative study of the effects of clofibrate, ciprofibrate, WY14.643, and di-[2-ethylhexyl)-phthalate on liver protein expression in mice. Appl. Theoret Electrophoresis 1991 2 101-107. 

The answer is a. (Hardman, pp 885-8870 Lovastatin should not be used in patients with severe liver disease. With routine use of lovastatin, serum transaminase values may rise, and in such patients the drug may be continued only with great caution. Lovastatin has also been associated with lenticular opacities, and slit-lamp studies should be done before and one year after the start of therapy There is no effect on the otic nerve. The drug is not toxic to the renal system, and reports of bone marrow depression are very rare There is a small incidence of myopathy, and levels of creatinine kinase should be measured when unexplained muscle pain occurs. Combination with cyclosporine or clofibrate has led to myopathy There is no danger in use with bile acid sequestrants. 

CNIOI Van Lith, H. A., M. Haller, G. Van Tintelen, A. G. Lemmens, L. E. Van Zutphen, and A. C. Beynen. Eat intake and clofibrate administration have interrelated effects on liver cholesterol concentration and serum butyryl cholinesterase activity in rats. J Nutr 1992 122(11) 2283-2291. 

Mizuguchi, H., Kudo, N., Ohya, T. Kawashima, Y. (1999) Effects of tiadenol and di-(2-ethyl-hexyl)phthalate on the metabolism of phosphatidylcholine and phosphatidylethanolamine in the liver of rats comparison with clofibric acid. Biochem. Pharmacol, 57, 869-876 Mocchiutti, N.O. Bernal, C.A. (1997) Effects of chronic di(2-ethylhexyl) phthalate intake on the secretion and removal rate of triglyceride-rich lipoproteins in rats. Food chem. Toxicol, 35, 1017-1021... 

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. 

Van Den Munckhof RJM, Bosch KS, Frederiks WM. 1998. The different effects of the peroxisome proliferators clofibric acid and bis(2-ethylhexyl)phthalate on the activities of peroxisomal oxidases in rat liver. Histochem J 30 339-349. 

The antipsychotic chlorpromazine is a prototype heptotoxicant for production of cholestasis. Pleiotropic effects of chlorpromazine on membrane permeability and associated ion gradients and microfilament-mediated canalicular contraction have been attributed to detergent effects. Valproic acid, an anticonvulsant, is associated with microvesicular steatosis. Inhibition of mitochondial fatty acid (S-oxidation is an important component of this toxic effect and is apparently related to carnitine availability as evidenced by the protection afforded by L-carnitine supplements. The hypolipidemic drugs clofibrate, fenofibrate, and gemfibrozil are peroxisome prolif-erators in rodent liver, but not in humans. Isoniazid, an antibiotic used to treat tuberculosis, exhibits an approximately 1 % incidence of hepatotoxicity. Although toxicity is known to be metabolism-dependent and protein adduction has been well-... 

Veitch K, Draye JP, Van Hoof F, and Sherratt HS (1988) Effects of riboflavin deficiency and clofibrate treatment on the five acyl-CoA dehydrogenases in rat liver mitochondria. 

Kramer JA, Blomme EA, Bunch RT, Davila JC, Jackson CJ, Jones PF, Kolaja KL, Curtiss SW. Transcription profiling distinguishes dose-dependent effects in the livers of rats treated with clofibrate. Toxicol Pathol 2003 31(4) 417-31. 

Osmundsen H, Cervenka J. Bremer J. Arole for 2,4-enoyl-CoA reductase in mitochondrial fl-oxidalion of polyunsaturated fatty acids. Effects of treatment with clofibrate on oxidation of polyunsaturated acylcarnitines by isolated rat liver. Biochem J 1982 208 749-757. 

Barrass, N. C, Price, R. J., Lake, B. G., and Orton, T. C. (1993). Comparison of the acute and chronic mitogenic effects of the peroxisome proliferators methylclofenapate and clofibric acid in rat liver. Carcinogenesis 14, 1451-1456. 

A. Mechanism and Effects Fibric acid derivatives (eg, gemfibrozil, fenofibrate, clofibrate) are ligands for the peroxisome proliferator-activated receptor-alpha (PPAR-a) protein, a receptor that regulates transcription of genes involved in lipid metabolism. Tbis interaction with PPAR-a results in increased activity of lipoprotein lipase and enhanced clearance of triglyceride-rich lipoproteins (Figure 35-2). Cholesterol biosynthesis in the liver is seeondarily reduced. The fibrates reduce serum triglyceride concentrations (Table 35-3). There may be a small reduction in LDL cholesterol and a small increase in HDL levels. 

Berge, R.K., Skrede, S. Farstad, M. (1981) Febs Lett. 124, 43-47. Effects of clofibrate on the intracellular localization of palmitoyl-CoA hydrolase and palmitoyl-L-camitine hydrolase in rat liver. 

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