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The Role of Nuclear Receptors in the Regulation of P450s and Other Genes by Peroxisome Proliferators

  • Conference paper
Molecular Aspects of Oxidative Drug Metabolizing Enzymes

Part of the book series: NATO ASI Series ((ASIH,volume 90))

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Abstract

Peroxisome proliferators are a large and varied group of chemicals that can induce P450s as well as other drug metabolizing enzymes. These chemicals can cause the number of peroxisomes in the livers of some sensitive species to increase with subsequent enlargement of the liver. This may ultimately lead to the development of liver tumors, but peroxisome proliferators or their metabolites do not appear to be mutagens (Rao, Reddy, 1991). Thus, they are considered to be non-genotoxic carcinogens. The increase in peroxisomes may in turn reflect the induction of several peroxisomal enzymes that metabolize fatty acids by β-oxidation. In contrast to mitochondrial β-oxidation, the peroxisomal pathway appears to function as pathway for the elimination of fatty acids and the production of heat rather than conservation of energy through the formation of ATP. In addition, long-chain, branched chain and dicarboxylic fatty acids are preferentially metabolized by the peroxisomal pathway. The latter can arise via the ω-hydroxylation of monocarboxylic acids, a reaction that is catalyzed by microsomal P450s of the CYP4A family and subsequent oxidation of the alcohol to a second carboxyl moiety by other enzymes.

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References

  • Bardot O, Aldridge TC, Latruffe N, Green S (1993) PPAR-RXR heterodimer activates a peroxisome proliferator response element upstream of the bifunctional enzyme gene. Biochem Biophys Res Commun 192: 37–45

    Article  PubMed  CAS  Google Scholar 

  • Bell DR, Elcombe CR (1991) Induction of acyl-CoA oxidase and cytochrome P450IVA1 RNA in rat primary hepatocyte culture by peroxisome proliferators. Biochem J 280: 249–253

    PubMed  CAS  Google Scholar 

  • Bugge TH, Pohl J, Lonnoy O, Stunnenberg HG (1992) RXRa, a promiscuous partner of retinoic acid and thyroid hormone receptors. EMBO J 11: 1409–1418

    PubMed  CAS  Google Scholar 

  • Carlberg C, Bendik I, Wyss A, Meier E, Sturzenbecker LJ, Grippo JF, Hunziker W (1993) Two nuclear signalling pathways for vitamin D. Nature 361: 657–660

    Article  PubMed  CAS  Google Scholar 

  • Dreyer C, Krey G, Keller H, Givel F, Helftenbein G, Wahli W (1992) Control of the peroxisomal beta-oxidation pathway by a novel family of nuclear hormone receptors. Cell 68: 879–887

    Article  PubMed  CAS  Google Scholar 

  • Durand B, Saunders M, Leroy P, Leid M, Chambon P (1992) All- trans and 9-cis retinoic acid induction of CRABPII transcription is mediated by RAR-RXR heterodimers bound to DR1 and DR2 repeated motifs. Cell 71: 73–85

    Article  PubMed  CAS  Google Scholar 

  • Funder JW (1993) Mineralocorticoids, glucocorticoids, receptors and response elements. Science 259: 1132–1133

    Article  PubMed  CAS  Google Scholar 

  • Gibson GG (1992) Co-induction of cytochrome P4504A1 and peroxisome proliferation: A causal or casual relationship. Xenobiotica 22: 1101–1109

    Article  PubMed  CAS  Google Scholar 

  • Göttlicher M, Widmark E, Li Q, Gustafsson J-A (1992) Fatty acids activate a chimera of the clofibric acid-activated receptor and the glucocorticoid receptor. Proc Natl Acad Sci USA 89: 4653–4657

    Article  PubMed  Google Scholar 

  • Hallenbeck PL, Marks MS, Lippoldt RE, Ozato K, Nikodem VM (1992) Heterodimerization of thyroid hormone (TH) receptor with H-2RIIBP ( RXRß) enhances DNA binding and TH-dependent transcriptional activation. Proc Natl Acad Sci USA 89: 5572–5576

    Article  PubMed  CAS  Google Scholar 

  • Husmann M, Hoffmann B, Stump DG, Chytil F, Pfahl M (1992) A retinoic acid response element from the rat CRBPI promoter is activated by an RAR/RXR heterodimer. Biochem Biophys Res Commun 187: 1558–1564

    Article  PubMed  CAS  Google Scholar 

  • Issemann I, Prince R, Tugwood J, Green S (1992) A role for fatty acids and liver fatty acid binding protein in peroxisome proliferation. Biochem Soc Trans 20: 824–827

    PubMed  CAS  Google Scholar 

  • Issemann I, Green S (1990) Activation of a member of the steroid hormone receptor superfamily by peroxisome proliferators. Nature 347: 645–650

    Article  PubMed  CAS  Google Scholar 

  • Johnson EF, Walker DW, Griffin KJ, Clark JE, Okita RT, Muerhoff AS, Masters BS (1990) Cloning and expression of three rabbit kidney cDNAs encoding lauric acid omega-hydroxylases. Biochemistry 29: 873–879

    Article  PubMed  CAS  Google Scholar 

  • Kaikaus RM, Chan WK, Lysenko N, Ray R, Ortiz de Montellano PR, Bass NM (1993) Induction of peroxisomal fatty acid ß-oxidation and liver fatty acid-binding protein by peroxisome proliferators. Mediation via the cytochrome P-450IVA1 omega-hydroxylase pathway. J Biol Chem 268: 9593–9603

    PubMed  CAS  Google Scholar 

  • Keller H, Dreyer C, Medin J, Mahfoudi A, Ozato K, Wahli W (1993) Fatty acids and retinoids control lipid metabolism through activation of peroxisome proliferator-activated receptor-retinoid X receptor heterodimers. Proc Natl Acad Sci USA 90: 2160–2164

    Article  PubMed  CAS  Google Scholar 

  • Kliewer SA, Umesono K, Noonan DJ, Heyman RA, Evans RM (1992) Convergence of 9-cis retinoic acid and peroxisome proliferator signalling pathways through heterodimer formation of their receptors. Nature 358: 771–774

    Article  PubMed  CAS  Google Scholar 

  • Ladias JA A, Hadzopoulou-Cladaras M, Kardassis D, Cardot P, Cheng J, Zannis V, Cladaras C (1992) Transcriptional regulation of human apolipoprotein genes ApoB, ApoCIII, and ApoAII by members of the steroid hormone receptor superfamily HNF-4, ARP-1, EAR-2, and EAR-3. J Biol Chem 267: 15849–15860

    PubMed  CAS  Google Scholar 

  • Ladias JAA, Karathanasis SK (1991) Regulation of the apolipoprotein AI gene by ARP-1, a novel member of the steroid receptor superfamily. Science 251: 561–565

    Article  PubMed  CAS  Google Scholar 

  • Lock EA, Mitchell AM, Elcombe CR (1989) Biochemical mechanisms of induction of hepatic peroxisome proliferation. Annu Rev Pharmacol Toxicol 29: 145–163

    Article  PubMed  CAS  Google Scholar 

  • Luisi BF, Xu WX; Otwinowski Z, Freedman LP, Yamamoto KR, Sigler PB (1991) Crystallographic analysis of the interaction of the glucocorticoid receptor with DNA. Nature 352: 497–505

    Article  PubMed  CAS  Google Scholar 

  • Masters BSS, Clark JE, Roman LJ, McCabe TJ, Helm CB, Johnson EF, Ma Y-H, Kauser K, Harder DR, Roman RJ (1992) Structure-Function studies and physiological roles of eicosanoids metabolized by cytochrome P450 omega-hydroxylases. In: Bailey JM (ed) Prostaglandins, Leukotrienes, Lipoxins and PAF. Plenum Publishing Co. New York pp 59–66

    Google Scholar 

  • Matsubara S, Yamamoto S, Sogawa K, Yokotani N, Fujii-Kuriyama Y, Haniu M, Shively JE, Gotoh O, Kusunose E, Kusunose M (1987) cDNA cloning and inducible expression during pregnancy of the mRNA for rabbit pulmonary prostaglandin omega-hydroxylase (cytochrome P-450 p-2). J Biol Chem 262: 13366–13371

    Google Scholar 

  • Muerhoff AS, Williams DE, Leithauser MT, Jackson VE, Waterman MR, Masters BSS (1987) Regulation of the induction of a cytochrome P-450 prostaglandin omega-hydroxylase by pregnancy in rabbit lung. Proc Natl Acad Sci 84: 7911–7914

    Article  PubMed  CAS  Google Scholar 

  • Muerhoff AS, Griffin KJ, Johnson EF (1992) The peroxisome proliferator activated receptor mediates the induction of CYP4A6, a cytochrome P450 fatty acid omega-hydroxylase, by clofibric acid. J Biol Chem 267: 19051–19053

    PubMed  CAS  Google Scholar 

  • Osumi T, Wen J-K, Hashimoto T (1991) Two cis-acting regulatory sequences in the peroxisome proliferator-responsive enhancer region of rat acyl-CoA oxidase gene. Biochem Biophys Res Commun 175: 866–871

    Article  PubMed  CAS  Google Scholar 

  • Palmer CNA, Griffin KJ, Johnson EF (1993a) Rabbit prostaglandin omega-hydroxylase (CyP4A4): Gene structure and expression. Arch Biochem Biophys 300: 670–676

    Article  PubMed  CAS  Google Scholar 

  • Palmer CNA, Hsu M-H, Muerhoff AS, Griffin KJ, Johnson EF (1993b) RXRa reveals a cryptic PPAR responsive element in the CYP4A6 promoter. FASEB J 7: A1166

    Google Scholar 

  • Rao MS, Reddy JK (1991) An overview of peroxisome proliferator-induced hepatocarcinogenesis. Environ Health Perspect 93: 205–209

    Article  PubMed  CAS  Google Scholar 

  • Schmidt A, Endo N, Rutledge SJ, Vogel R, Shinar D, Rodan GA (1992) Identification of a new member of the steroid hormone receptor superfamily that is activated by a peroxisome proliferator and fatty acids. Mol Endocrinol 6: 1634–1641

    Article  PubMed  CAS  Google Scholar 

  • Schwartzman ML, Falck JR, Yadagiri P, Escalante B (1989) Metabolism of 20-hydroxyeicosatetraenoic acid by cyclooxygenase. J Biol Chem 264: 11658–11662

    PubMed  CAS  Google Scholar 

  • Sher T, Yi H-F, McBride OW, Gonzalez FJ (1993) cDNA cloning, chromosomal mapping, and functional characterization of the human peroxisome proliferator activated receptor. Biochemistry 32: 5598–5604

    Google Scholar 

  • Tugwood JD, Issemann I, Anderson RG, Bundell KR, McPheat WL, Green S (1992) The mouse peroxisome proliferator activated receptor recognizes a response element in the 5’ flanking sequence of the rat acyl CoA oxidase gene. EMBO J 11: 433–439

    PubMed  CAS  Google Scholar 

  • Williams DE, Hale SE, Okita RT, Masters BSS (1984) A prostaglandin omega-hydroxylase cytochrome P-450 (P-450 PG-omega) purified from lungs of pregnant rabbits. J Biol Chem 259: 14600 - 14608

    PubMed  CAS  Google Scholar 

  • Yamamoto S, Kusunose E, Ogita K, Kaku M, Ichihara K, Kusunose M (1984) Isolation of cytochrome P-450 highly active in prostaglandin omega-hydroxylation from lung microsomes of rabbits treated with progesterone. J Biochem 96: 593–603

    PubMed  CAS  Google Scholar 

  • Yokotani N, Bernhardt R, Sogawa K, Kusunose E, Gotoh O, Kusunose M, Fujii-Kuriyama Y (1989) Two forms of omega-hydroxylase toward prostaglandin A and laurate. J Biol Chem 264: 21665–21669

    PubMed  CAS  Google Scholar 

  • Yokotani N, Kusunose E, Sogawa K, Kawashima H, Kinosaki M, Kusunose M, Fujii-Kuriyama Y (1991) cDNA cloning and expression of the mRNA for cytochrome P-450 which shows a fatty acid omega-hydroxylating activity. Eur J Biochem 196: 531–536

    Google Scholar 

  • Zhang B, Marcus SL, Sajjadi FG, Alvares K, Reddy JK, Subramani S, Rachubinski RA, Capone JP (1992) Identification of a peroxisome proliferator-responsive element upstream of the gene encoding rat peroxisomal enoyl-CoA hydratase/3- hydroxyacyl-CoA dehydrogenase. Proc Natl Acad Sci USA 89: 7541–7545

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Division of Biochemistry, NX-4, The Scripps Research Institute, 10666 North Torrey Pines Road, La Jolla, CA, 92037, USA

    Eric F. Johnson, Colin N. A. Palmer, Mei-H. Hsu & Keith J. Griffin

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  1. Eric F. Johnson
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  2. Colin N. A. Palmer
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  3. Mei-H. Hsu
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  4. Keith J. Griffin
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Editor information

Editors and Affiliations

  1. Department of Biology, Middle East Technical University, Inönü Bulvari, Ankara, 06531, Turkey

    Emel Arinç

  2. Department of Toxicology, University of Connecticut Health Center, Farmington, Connecticut, 06032, USA

    John B. Schenkman

  3. Department of Toxicology, North Carolina State University, Raleigh, North Carolina, 27695, USA

    Ernest Hodgson

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© 1995 Springer-Verlag Berlin Heidelberg

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Johnson, E.F., Palmer, C.N.A., Hsu, MH., Griffin, K.J. (1995). The Role of Nuclear Receptors in the Regulation of P450s and Other Genes by Peroxisome Proliferators. In: Arinç, E., Schenkman, J.B., Hodgson, E. (eds) Molecular Aspects of Oxidative Drug Metabolizing Enzymes. NATO ASI Series, vol 90. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-79528-2_5

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  • DOI: https://doi.org/10.1007/978-3-642-79528-2_5

  • Publisher Name: Springer, Berlin, Heidelberg

  • Print ISBN: 978-3-642-79530-5

  • Online ISBN: 978-3-642-79528-2

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