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Arzneimittelforschung 2008; 58(5): 225-241
DOI: 10.1055/s-0031-1296499
Lipid Regulating Agents
Editio Cantor Verlag Aulendorf (Germany)

Ciprofibrate, Clofibric Acid and Respective Glycinate Derivatives

Effects of a four-week treatment on male lean and obese Zucker rats
Amelie Lupp
1   Institute of Pharmacology and Toxicology, Friedrich Schiller University, Jena, Germany
,
Elke Karge
1   Institute of Pharmacology and Toxicology, Friedrich Schiller University, Jena, Germany
,
Thomas Deufel
2   Institute of Clinical Chemistry and Laboratory Diagnostics, Friedrich Schiller University, Jena, Germany
,
Herbert Oelschläger
3   Institute of Pharmacy, Friedrich Schiller University, Jena, Germany
,
Christian Fleck
1   Institute of Pharmacology and Toxicology, Friedrich Schiller University, Jena, Germany
› Author Affiliations
Further Information

Publication History

Publication Date:
15 December 2011 (online)

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Abstract

Fibrates are widely prescribed in hyperipidemic patients to prevent atherosclerosis. Their therapeutic use, however, can be associated with adverse effects like gastrointestinal disorders, myalgia, myositis, and hepatotoxicity. In rodents large doses can even cause hepatocellular carcinoma. Additionally, interactions with the biotransformation of other compounds at the cytochrome P450 (CYP) system have been observed. Thus, the discovery of new substances or derivatives with less side effects is of great interest.

In the present study the influence of a four-week daily oral administration of 2 mg/kg body weight ciprofibrate (CAS 52214–84–3) or of 100 mg/kg body weight clofibric acid (CAS 882–09–7) was compared to that of the respective doses of their newly synthesized glycine conjugates in adult male lean and obese Zucker rats.

Although obese rats displayed distinctly higher serum lipid concentrations, after fibrate treatment values were significantly lowered in lean animals only. Livers of obese rats were significantly enlarged, histologically showing a finedroplet like fatty degeneration and an increase in glycogen content, but no signs of inflammation. After fibrate administration histologically a hypertrophy, an eosinophilia, a reduced glycogen content and also hepatocyte apoptosis were observed. Livers of obese rats displayed higher CYP1A1 and CYP2E1 expression, but lower immunostaining for CYP2B1 and CYP3A2. No differences between the two groups of rats were seen with respect to CYP4A1 expression. Due to fibrate treatment especially CYP2E1 and CYP–4A1, but also CYP1A1,2B1 and 3A2 were induced. Resulting CYP mediated monooxygenase activities were also elevated in most cases.

In general, effects of clofibric acid and clofibric acid glycinate (CAS 4896-55-3) were less distinct than those of ciprofibrate and its glycinate (CAS 640772-36-7). With no parameter investigated major differences were seen between the parent fibrates and their glycine conjugates. Thus, the present investigations revealed no noticeable advantages of the glycinates over ciprofibrate or clofibric acid.

Key words

Ciprofibrate, glycine conjugate, obese Zucker rats - Clofibric acid, glycine conjugate, obese Zucker rats - Cytochrome P450 - Fibrates - Lipid regulating agents
 

  • References

  • 1 Rizzo M, Berneis K. The clinical significance of the size of lowdensity-lipoproteins and the modulation of subclasses by fibrates. Curr Med Res Opin. 2007; 23: 1103-1111
    CrossrefPubMedGoogle Scholar
  • 2 Ascaso J, Gonzalez-Santos P, Hernandez-Mijares A, Mangas-Rojas A, Masana L, Millan J et al. Management of dys-lipidemia in the metabolic syndrome: recommendations of the Spanish HDL-Forum. Am J Cardiovasc Drugs. 2007; 7: 39-58
    CrossrefPubMedGoogle Scholar
  • 3 Garg A, Simha V. Update on dyslipidemia. J Clin EndocrinolMetab. 2007; 92: 1581-1589
    CrossrefPubMedGoogle Scholar
  • 4 Oh RC, Lanier JB. Management of hypertriglyceridemia. Am Family Phys. 2007; 75: 1365-1371
    PubMedGoogle Scholar
  • 5 Bianchi C, Penno G, Romero F, Del Prato S, Miccoli R. Treating the metabolic syndrome. Exp Rev Cardiovasc Ther. 2007; 5: 491-506
    CrossrefPubMedGoogle Scholar
  • 6 Backes JM, Gibson CA, Ruisinger JF, Moriarty PM. Fibrates: what we have learned in the past 40 years?. Pharmacother. 2007; 27: 412-424
    CrossrefPubMedGoogle Scholar
  • 7 Yuan G, Al-Shali KZ, Hegele RA. Hypertriglyceridemia: its etiology effects and treatment. CMAJ. 2007; 176: 1113-1120
    CrossrefPubMedGoogle Scholar
  • 8 Jones PH. Clinical significance of recent lipid trials on reducing risk in patients with type 2 diabetes mellitus. Am J Cardiol. 2007; 99: 133B-140B
    CrossrefPubMedGoogle Scholar
  • 9 Robins SJ, Bloomfield HE. Fibric acid derivatives in cardiovascular disease prevention: results from the large trials. Curr Opin Lipidol. 2006; 17: 431-439
    PubMedGoogle Scholar
  • 10 Tenenbaum A, Fishman EZ, Motro M, Adler Y. Atherogenic dyslipidemia in metabolic syndrome and type 2 diabetes: therapeutic options beyond statins. Cardiovasc Diabetol. 2006; 5: 20
    CrossrefPubMedGoogle Scholar
  • 11 Cignarella A, Bellosta S, Corsini A, Bolego C. Hypolipidemic therapy for the metabolic syndrome. Pharmacol Res. 2006; 53: 492-500
    CrossrefPubMedGoogle Scholar
  • 12 Robins SJ. Lipid therapy for cardiovascular disease with insulin resistance, diabetes, or the metabolic syndrome. Curr Cardiol Rep. 2005; 7: 457-464
    CrossrefPubMedGoogle Scholar
  • 13 Davidson MH, Armani A, McKenney JM, Jacobson TA. Safety considerations with fibrate therapy. Am J Cardiol. 2007; 99 (Suppl) 3C-18C
    PubMedGoogle Scholar
  • 14 Reddy JK, Azarnoff DL, Hignite CE. Hypolipidaemic hepatic peroxisome proliferators form a novel class of chemical carcinogens. Nature. 1980; 283: 397-398
    CrossrefPubMedGoogle Scholar
  • 15 Cohen AJ, Grasso R. Review of the hepatic response to hypolipidaemic drugs in rodents and assessment of its toxi-cological significance to man. Food Cosmet Toxicol. 1981; 19: 585-605
    CrossrefPubMedGoogle Scholar
  • 16 Peters JM, Cheung C, Gonzalez FJ. Peroxisome prolifera-tor-activated receptor-alpha and liver cancer: where do we stand?. J Mol Med. 2005; 83: 774-785
    CrossrefPubMedGoogle Scholar
  • 17 Corton JC, Lapinskas PJ, Gonzalez FJ. Central role of PPARalpha in the mechanism of action of hepatocarcinogenic peroxisome proliferators. Mutat Res. 2000; 448: 139-151
    PubMedGoogle Scholar
  • 18 Willson TM. The PPARs: From orphan receptors to drug discovery. J Med Chem. 2000; 43: 527-550
    CrossrefPubMedGoogle Scholar
  • 19 Cornwell PD, De Souza AT, Ulrich RG. Profiling of hepatic gene expression in rats treated with fibric acid analogs. Mutat Res. 2004; 549: 131-145
    PubMedGoogle Scholar
  • 20 Chinetti-Gbaguidi G, Fruchart JC, Staels B. Pleiotropic effects of fibrates. Curr Atheroscl Rep. 2005; 7: 396-401
    CrossrefPubMedGoogle Scholar
  • 21 Robillard R, Fontaine C, Chinetti G, Fruchart JC, Staels B. Fibrates. Handbook Exp Pharmacol. 2005; 170: 389-406
    PubMedGoogle Scholar
  • 22 Fruchart JC, Duriez P. Mode of action of fibrates in the regulation of triglyceride and HDL-cholesterol metabolism. Drugs of Today. 2006; 42: 39-64
    CrossrefPubMedGoogle Scholar
  • 23 DePierre JW, Sohlenius AK, Cai Y, Eriksson AM, Andersson K, Sundberg C. Peroxisome proliferation in response to xenobiotics. Biochem Soc Transact. 1995; 23: 425-429
    PubMedGoogle Scholar
  • 24 Graham MJ, Winham MA, Old SL, Gray TJB. Comparative hypolipidaemic and peroxisomal effects of ciproflbrate, clofibric acid, and their respective difluorocyclopropyl and 4-fluorosubstituted analogues in rat. Xenobiotica. 1996; 26: 695-707
    CrossrefPubMedGoogle Scholar
  • 25 Yaacob NS, Norazmi MN, Kass GEN, Gibson GG. Use of competitive RT-PCR in the molecular analysis of peroxisome proliferation. Eur J Drug Metab Pharmacokin. 1997; 22: 321-324
    CrossrefPubMedGoogle Scholar
  • 26 Nemali MR, Reddy MK, Usuda N, Reddy PG, Comeau LD, Rao MS et al. Differential induction and regulation of peroxisomal enzymes: predictive value of peroxisome proliferation in identifying certain nonmutagenic carcinogens. Toxicol Appl Pharmacol. 1989; 97: 72-87
    CrossrefPubMedGoogle Scholar
  • 27 Reddy JK, Lalwani ND, Qureshi SA, Reddy MK, Moehle CM. Induction of hepatic peroxisome proliferation in non-rodent species, including primates. Am J Pathol. 1984; 114: 171-183
    PubMedGoogle Scholar
  • 28 Makowska JM, Bonner FW, Gibson GG. Comparative induction of cytochrome P450IVA1 and peroxisome proliferation by ciproflbrate in the rat and marmoset. Arch Toxicol. 1991; 65: 106-113
    CrossrefPubMedGoogle Scholar
  • 29 Makowska JM, Gibson GG, Bonner FW. Species differences in ciproflbrate induction of hepatic cytochrome P450 4A1 and peroxisome proliferation. J Biochem Toxicol. 1992; 7: 183-191
    CrossrefPubMedGoogle Scholar
  • 30 Graham MJ, Wilson SA, Winham MA, Spencer AJ, Rees JA, Old SL et al. Lack of peroxisome proliferation in marmoset liver following treatment with ciproflbrate for three years. Fundam Appl Toxicol. 1994; 22: 58-64
    CrossrefPubMedGoogle Scholar
  • 31 Holden PR, Tugwood JD. Peroxisome proliferator-activated receptor alpha: role in rodent liver cancer and species differences. J Mol Endocrinol. 1999; 22: 1-8
    CrossrefPubMedGoogle Scholar
  • 32 Lake BG, Rumsby PC, Price RJ, Cunninghame ME. Species differences in hepatic peroxisome proliferation, cell replication and transforming growth factor-ßl gene expression in the rat, Syrian hamster and guinea pig. Mutat Res. 2000; 448: 213-225
    PubMedGoogle Scholar
  • 33 Rodriguez C, Noe V, Cabrero A, Ciudad CJ, Laguna JC. Differences in the formation of PRARalpha-RXR / acoPPRE complexes between responsive and nonresponsive species upon Abrate administration. Mol Pharmacol. 2000; 58: 185-193
    PubMedGoogle Scholar
  • 34 Ammerschlaeger M, Beigel J, Klein KU, Mueller SO. Characterization of the species-specificity of peroxisome proliferators in rat and human hepatocytes. Toxicol Sci. 2004; 78: 229-240
    CrossrefPubMedGoogle Scholar
  • 35 Boiteux-Antoine AF, Magdalou J, Fournel-Gigleux S, Siest G. Comparative induction of drug-metabolizing enzymes by hypolipidaemic compounds. Gen Pharmac. 1989; 20: 407-412
    CrossrefPubMedGoogle Scholar
  • 36 Makowska JM, Anders C, Goldfarb PS, Bonner F, Gibson GG. Characterization of the hepatic responses to the short-term administration of ciproflbrate in several rat strains. Co-induction of microsomal cytochrome P-450 IVA1 and peroxisome proliferation. Biochem Pharmacol. 1990; 40: 1083-1093
    CrossrefPubMedGoogle Scholar
  • 37 Gibson GG, Lake BG. Induction protocols for the cytochrome P450IVA subfamily in animals and primary hepatocyte cultures. Meth Enzymol. 1991; 206: 353-363
    PubMedGoogle Scholar
  • 38 Zangar RC, Woodcroft KJ, Kocarek TA, Novak RF. Xenobiotic-enhanced expression of cytochrome P450 2E and 2B1/2B2 in primary cultured rat hepatocytes. DrugMetab Dispos. 1995; 23: 681-687
    PubMedGoogle Scholar
  • 39 Zangar RC, Woodcroft KJ, Novak RF. Differential effects of ciprofibrate on renal and hepatic cytochrome P450 2E1 expression. Toxicol Appl Pharmacol. 1996; 141: 110-116
    PubMedGoogle Scholar
  • 40 Lake BG, Charzat C, Tredger JM, Renwick AB, Beamand JA, Price RJ. Induction of cytochrome P450 isoenzymes in cultured precision-cut rat and human liver slices. Xenobiotica. 1996; 26: 297-306
    CrossrefPubMedGoogle Scholar
  • 41 Lozada A, Dujovne CA. Drug interactions with fibric acids. Pharmacol Ther. 1994; 63: 163-176
    CrossrefPubMedGoogle Scholar
  • 42 Bays HE, Dujovne CA. Drug interactions of lipid-altering drugs. Drug Saf. 1998; 19: 355-371
    CrossrefPubMedGoogle Scholar
  • 43 Miller DB, Spence JD. Clinical pharmacokinetics of fibric acid derivatives (fibrates). Clin Pharmacokinet. 1998; 34: 155-162
    CrossrefPubMedGoogle Scholar
  • 44 Davidson MH. Statin/fibrate combination in patients with metabolic syndrome or diabetes: evaluating the risk of pharmacokinetic drug interactions. Exp Opin Drug Saf. 2006; 5: 145-156
    CrossrefPubMedGoogle Scholar
  • 45 Lupp A, Karge E, Danz M, Deufel T, Oelschläger H, Klinger W. Single and chronic administration of ciprofibrate or of ciprofibrate glycinate in male Fischer 344 rats: comparison of the effects on morphological and biochemical parameters in liver and blood. Eur J Drug Metab Pharmacokinet. 2005; 30: 203-218
    CrossrefPubMedGoogle Scholar
  • 46 Argiles JM. The obese Zucker rat: a choice for fat metabolism. 1968-1988: twenty years of research on the insights of the Zucker mutation. Prog Lipid Res. 1989; 28: 53-66
    CrossrefPubMedGoogle Scholar
  • 47 Kasiske B, O’Donnell MP, Keane W. The Zucker rat model of obesity, insulin resistance, hyperlipidemia, and renal injury. Hypertension. 1992; 19 (Suppl I) 110-115
    CrossrefPubMedGoogle Scholar
  • 48 Guerre-Millo M. Regulation of ob gene and overexpression in obesity. Biomed Pharmacother. 1997; 51: 318-323
    CrossrefPubMedGoogle Scholar
  • 49 Koteish A, Diehl AM. Animal models of steatohepatitis. Best Pract Res Clin Gastroenterol. 2002; 16: 679-690
    CrossrefPubMedGoogle Scholar
  • 50 Tofovic SP, Jackson EK. Rat models of the metabolic syndrome. Methods Mol Med. 2003; 86: 29-46
    PubMedGoogle Scholar
  • 51 Chen D, Wang MW. Development and application of rodent models for type 2 diabetes. Diabetes, Obesity and Metabolism. 2005; 7: 307-317
    CrossrefPubMedGoogle Scholar
  • 52 Burke MD, Thompson S, Weaver RJ, Wolf CR, Mayer RT. Cytochrome P450 specificities of alkoxyresorufin O-deal-kylation in human and rat liver. Biochem Pharmacol. 1994; 48: 923-936
    CrossrefPubMedGoogle Scholar
  • 53 Correia MA. Rat and human liver cytochrome P450: substrate and inhibitor specificities and functional markers. In: Ortiz de Montellano PR. ed. Cytochrome P450: structure, mechanism and biochemistry. 2nd ed. New York and London: Plenum Press; 1995. p. 607-630
    Google Scholar
  • 54 Smolowitz RM, Hahn ME, Stegeman JJ. Immunohis-tochemical localization of cytochrome P-450IA1 induced by 3,3’,4,4’-tetrachlorobiphenyl and by 2,3,7,8-tetrachlorodibenzofuran in liver and extrahepatic tissues of the te-leost Stenotomus chrysops (scup). Drug Metab Dispos. 1991; 19: 113-123
    PubMedGoogle Scholar
  • 55 Lupp A, Danz M, Müller D. Morphology and cytochrome P450 isoforms expression in precision-cut rat liver slices. Toxicology. 2001; 161: 53-66
    CrossrefPubMedGoogle Scholar
  • 56 Yagi K. Lipid peroxides and human diseases. Chem Phys Lipids. 1987; 45: 337-351
    CrossrefPubMedGoogle Scholar
  • 57 Ellman GL. Tissue sulfhydryl groups. Arch Biochem Biophys. 1959; 82: 70-77
    CrossrefPubMedGoogle Scholar
  • 58 Hissin PJ, Hilf R. A fluorometric method for determination of oxidized and reduced glutathione in tissues. Anal Biochem. 1976; 74: 214-226
    CrossrefPubMedGoogle Scholar
  • 59 Stratford MRL, Watfa RR, Murray C, Martin SG. Determination of collagen and protein turnover by high-performance liquid chromatography. J Chromatogr. 1990; 529: 383-395
    PubMedGoogle Scholar
  • 60 Klinger W, Müller D. The influence of age on the protein concentration in serum, liver, and kidney of rats determined by various methods. Z Versuchstierk. 1974; 16: 146-153
    PubMedGoogle Scholar
  • 61 Matsubara T, Otsubo S, Yoshihara E. Liver microsomal cytochrome P-450-dependent O-dealkylation reaction in various animals. Jpn J Pharmacol. 1983; 33: 1065-1075
    CrossrefPubMedGoogle Scholar
  • 62 Pohl RJ, Fouts JR. A rapid method for assaying the metabolism of 7-ethoxyresorufin by microsomal subcellular fractions. Anal Biochem. 1980; 107: 150-155
    CrossrefPubMedGoogle Scholar
  • 63 Aitio A. A simple and sensitive assay of 7-ethoxycoumarin deethylation. Anal Biochem. 1978; 85: 488-491
    CrossrefPubMedGoogle Scholar
  • 64 Chang TKH, Crespi CL, Waxman DJ. Spectrophotometric analysis of human CYP2E1-catalyzed p-nitrophenol hydroxylation. In: Phillips IR, Shephard EA. eds. Methods in molecular biology. Vol. 107. Cytochrome P450 protocols 1997. p. 147-152
    Google Scholar
  • 65 Nash T. The colorimetric estimation of formaldehyde by means of the Hantzsch reaction. Biochem J. 1953; 55: 416-421
    PubMedGoogle Scholar
  • 66 Klinger W, Müller D. Ethylmorphine N-demethylation by liver homogenate of newborn and adult rats; enzyme kinetics and age course of Vmax and Km. Acta Biol Med Germ. 1977; 36: 1149-1159
    PubMedGoogle Scholar
  • 67 Dirven HAAM, De Bruijn AAGM, Sessink PJM, Jongeneelen FJ. Determination of the cytochrome P-450 IV marker, ω-hydroxylauric acid, by high-performance liquid chromatography and fluorimetric detection. J Chromatogr. 1991; 564: 266-271
    CrossrefPubMedGoogle Scholar
  • 68 Young JK, Fleming MW, Matsumoto DE. Sex behavior and the sexually dimorphic hypothalamic nucleus in male Zucker rats. Physiol Behav. 1986; 36: 881-886
    CrossrefPubMedGoogle Scholar
  • 69 Serfass RE, Park KE, Kaplan ML. Developmental changes of selected minerals in Zucker rats. Proc Soc Exp Biol Med. 1988; 189: 229-239
    PubMedGoogle Scholar
  • 70 Winocur G, Greenwood CE, Piroli GG, Grillo CA, Reznikov LR, Reagan LP et al. Memory impairment in obese Zucker rats: an investigation of cognitive function in an animal model of insulin resistance and obesity. Behav Neurosci. 2005; 119: 1389-1395
    CrossrefPubMedGoogle Scholar
  • 71 Gustafson D, Rothenberg E, Blennow K, Steen B, Skoog I. An 18-year follow-up of overweight and risk of Alzheimer disease. Arch Intern Med. 2003; 163: 1524-1528
    CrossrefPubMedGoogle Scholar
  • 72 Kivipelto M, Ngandu T, Fratiglioni L, Viitanen M, Kareholt I, Winblad B et al. Obesity and vascular risk factors at midlife and the risk of dementia and Alzheimer disease. Arch Neurol. 2005; 62: 1556-1560
    CrossrefPubMedGoogle Scholar
  • 73 Razay G, Vreugdenhil A, Wilcock G. Obesity, abdominal obesity and Alzheimer disease. Dem Ger Cogn Dis. 2006; 22: 173-176
    PubMedGoogle Scholar
  • 74 Vanhanen M, Koivisto K, Moilanen L, Helkala EL, Hänninen T, Soininen H et al. Association of metabolic syndrome with Alzheimer disease. Neurology. 2006; 67: 843-847
    CrossrefPubMedGoogle Scholar
  • 75 Luchsinger JA, Jayeux R. Adiposity and Alzheimer’s disease. Curr Alzheimer Res. 2007; 4: 127-134
    CrossrefPubMedGoogle Scholar
  • 76 Jagust W. What can imaging reveal about obesity and the brain?. Curr Alzheimer Res. 2007; 4: 135-139
    CrossrefPubMedGoogle Scholar
  • 77 Abraham KM. Animal models of obesity and metabolic syndrome: potential tools for Alzheimer’s disease research. Curr Alzheimer Res. 2007; 4: 145-146
    CrossrefPubMedGoogle Scholar
  • 78 Charmoillaux M, Goudonnet H, Mercenne F, Mounie J, Truchot RC. Comparative and simultaneous effects of simvastatin and ciprofibrate on plasma lipid parameters and upon hepatic drug metabolizing and peroxisome proliferation marker enzymes in the male Wistar rat. Cell Mol Biol. 1991; 37: 765-771
    PubMedGoogle Scholar
  • 79 Close I, Shackleton G, Goldfarb PS, Gibson GG, Sharma R, Howes D. Influence of single and concurrent clofibric acid and phenobarbital administration on cytochrome P450-dependent mixed function oxidase activities and peroxisome proliferation in male rat liver. J Biochem Toxicol. 1992; 7: 193-198
    CrossrefPubMedGoogle Scholar
  • 80 Laight DW, Desai KM, Gopaul NK, Anggard EE, Carrier MJ. F2-isoprostane evidence of oxidant stress in the insulin resistant, obese Zucker rat: effects of vitamin E. Eur ] Pharmacol. 1999; 377: 89-92
    PubMedGoogle Scholar
  • 81 Carmiel-Haggai M, Cederbaum AI, Nieto N. Binge ethanol exposure increases liver injury in obese rats. Gastroenterol. 2003; 125: 1818-1833
    CrossrefPubMedGoogle Scholar
  • 82 Serkova NJ, Jackman M, Brown JL, Liu T, Hirose R, Roberts JP et al. Metabolic profiling of livers and blood from obese Zucker rats . J Hepatol. 2006; 44: 956-62
    CrossrefPubMedGoogle Scholar
  • 83 Pacot C, Petit M, Caira F, Rollin M, Behechti N, Gregoire S et al. Response of genetically obese Zucker rats to ciprofibrate, a hypolipidemic agent, with peroxisome proliferation activity as compared to Zucker lean and Sprague-Dawley rats. Biol Cell. 1993; 77: 27-35
    CrossrefPubMedGoogle Scholar
  • 84 Herbert JM, Bernat A, Chatenet-Duchène L. Effect of ciprofibrate on fibrinogen synthesis in vitro on hepatoma cells and in vivo in genetically obese Zucker rats. Blood Coagul Fibrinolysis. 1999; 10: 239-244
    PubMedGoogle Scholar
  • 85 Dana SL, Hoener PA, Bilakovics JM, Crombie DL, Ogilvie KM, Kauffman RF et al. Peroxisome proliferator-activated receptor subtype-specific regulation of hepatic and peripheral gene expression in the Zucker diabetic fatty rat. Metabolism. 2001; 50: 963-971
    CrossrefPubMedGoogle Scholar
  • 86 Zhao X, Quigley JE, Yuan J, Wang MH, Zhou Y, Imig JD. PPAR- α activator fenofibrate increases renal CYP-derived eicosanoid synthesis and improves endothelial dilator function in obese Zucker rats. Am J Physiol Heart Circ Physiol. 2006; 290: H2187-H2195
    CrossrefPubMedGoogle Scholar
  • 87 Cleary MP, Kasiske B, O’Donnell MP, Keane WF. Effect of long-term clofibric acid treatment on serum and tissue lipid and cholesterol levels in obese Zucker rats. Atherosclerosis. 1987; 66: 107-112
    CrossrefPubMedGoogle Scholar
  • 88 Kasiske BL, O’Donnell MP, Cleary MP, Keane WF. Treatment of hyperlipidemia reduces glomerular injury in obese Zucker rats. Kidney Int. 1988; 33: 667-672
    CrossrefPubMedGoogle Scholar
  • 89 Chaput E, Saladin R, Silvestre M, Edgar AD. Fenoflbrate and rosiglitazone lower serum triglycerides with opposing effects on body weight. Biochem Biophys Res Commun. 2000; 271: 445-450
    CrossrefPubMedGoogle Scholar
  • 90 Olivier P, Plancke MO, Theret N, Marzin D, Clavey V, Fruchart JC. Effects of fenoflbrate on lipoprotein metabolism and fatty acid distribution in Zucker rats. Atherosclerosis. 1988; 74: 15-21
    CrossrefPubMedGoogle Scholar
  • 91 Khemawoot P, Yokogawa K, Shimada T, Miyamoto K. Obesityinduced increase of CYP2E1 activity and its effect on disposition kinetics of choroxazone in Zucker rats. Biochem Pharmacol. 2007; 73: 155-162
    CrossrefPubMedGoogle Scholar
  • 92 Xiong H, Yoshinari K, Brouwer KLR, Negishi M. Role of constitutive androstane receptor in the in vivo induction of Mrp3 and CYP2B1/2 by phenobarbital. Drug Metab Dispos. 2002; 30: 918-923
    CrossrefPubMedGoogle Scholar
  • 93 Enriquez A, Leclercq I, Farrell GC, Robertson G. Altered expression of hepatic CYP2E1 and CYP4A in obese diabetic ob/ob mice fa/fa Zucker rats. Biochem Biophys Res Commun. 1999; 255: 300-306
    CrossrefPubMedGoogle Scholar
  • 94 Kotlyar M. Carson SW Effects of obesity on the cytochrome P450 enzyme system. Int J Clin Pharmacol Ther. 1999; 37: 8-19
    PubMedGoogle Scholar
  • 95 Irizar A, Barnett CR, Flatt PR, Ioannides C. Defective expression of cytochrome P450 proteins in the liver of the genetically obese Zucker rat. Eur J Pharmacol. 1995; 293: 385-393
    CrossrefPubMedGoogle Scholar
  • 96 Blouin RA, Bandyopadhyay AM, Chaudhary I, Robertson LW, Gemzik B, Parkinson A. Cytochrome P450 2B enzyme (CYP2B) induction defect following phenobarbital treatment in the fa/fa Zucker rat: molecular characterization. Arch Biochem Biophys. 1993; 303: 313-320
    CrossrefPubMedGoogle Scholar
  • 97 Huupponen R, Pyykko K, Ala-Uotila S, Sotaniemi E. Activity of xenobiotic metabolizing liver enzymes in Zucker rats. Res Comm Chem Path Pharmacol. 1991; 72: 307-314
    PubMedGoogle Scholar
  • 98 Zaluzny L, Farrell GC, Murray M. Effect of genetic obesity and experimental diabetes on hepatic microsomal mixed function oxidase activities. J Gastroenterol Hepatol. 1990; 5: 256-263
    CrossrefPubMedGoogle Scholar
  • 99 Gallagher EP, Buetler TM, Stapleton PL, Wang C, Stahl DL, Eaton DL. The effects of diquat and ciprofibrate on mRNA expression and catalytic activities of hepatic xenobiotic metabolizing and antioxidant enzymes in rat liver. Toxicol Appl Pharmacol. 1995; 134: 81-91
    CrossrefPubMedGoogle Scholar
  • 100 Richert L, Lamboley C, Viollon-Abadie C, Grass P, Hartmann N, Laurent S et al. Effects of clofibric acid on mRNA expression profiles in primary cultures of rat, mouse and human hepatocytes. Toxicol Appl Pharmacol. 2003; 191: 130-146
    CrossrefPubMedGoogle Scholar
  • 101 Shaban Z, El-Shazly S, Ishizuka M, Kimura K, Kazusaka A, Fujita S. PPARα-dependent modulation of hepatic CYP1A by clofibric acid in rats. Arch Toxicol. 2004; 78: 496-507
    PubMedGoogle Scholar
  • 102 Zannikos PN, Bandyopadhyay AM, Robertson LW, Blouin RA. Cytochrome P450 2B enzyme induction defect after 2,2’,4,4’,5,5’-hexachlorobiphenyl treatment in the fa/fa Zucker rat. J Pharmacol Exp Ther. 1994; 268: 1565-1570
    PubMedGoogle Scholar
  • 103 Lubet RA, Nims RW, Dragnev KH, Jones CR, Diwan BA, Devor DE et al. A markedly diminished pleiotropic response to phenobarbital and structurally-related xenobiotics in Zucker rats in comparison with F344/NCr or DA rats. Biochem Pharmacol. 1992; 43: 1079-1087
    CrossrefPubMedGoogle Scholar
  • 104 Brouwer KLR, Kostenbauder HB, McNamara PJ, Blouin RA. Phenobarbital in the genetically obese Zucker rat. II. In vivo and in vitro assessments of microsomal enzyme induction. J Pharmacol Exp Ther. 1984; 231: 654-659
    PubMedGoogle Scholar