Pseudolaric Acid Analogs as a New Class of Peroxisome Proliferator-Activated Receptor Agonists

 

 Buy Article Permissions and Reprints

Abstract

Extracts of the root and trunk barks of the Chinese tree Pseudolarix kaempferi, which contain pseudolaric acids, are used in Chinese medicine for treatment of fungal infections. Pseudolaric acid B (PLAB) is the major constituent that exhibits anti-fungal activity. The nuclear peroxisome proliferator-activator receptors (PPAR) were proposed as a cellular target for the action of PLAB and its analogs. PLAB and two derivatives were tested for the activation of PPAR isoforms in two mammalian cell lines. CV-1 and H4IIEC3 cells were transfected with phorbol ester response element or PPAR response element reporter constructs, and CV-1 cells were co-transfected with the individual PPAR isoform expression plasmids. PLAB showed similar concentration-dependent effects for the activation of PPAR α, γ and δ isoforms in CV-1 and H4IIEC3 cells. O-Deacetylation of PLAB (PLAC) or esterification of the free carboxy group of PLAB with β-D-O-glucopyranoside (PLAG) markedly reduced or abolished the activation of these PPAR isoforms. In H4IIEC3 cells, PLAB increased the activation of endogenous PPARα and the phospholipase C signaling pathway; and stimulated peroxisomal fatty acyl-CoA oxidase activity. These effects of PLAB on the activation of endogenous PPARα and phospholipase C-dependent pathway were blocked by staurosporine. These results suggest that the action of PLAB on PPARα in H4IIEC3 cells is mediated by a protein kinase C dependent phosphorylation. Based upon these findings, the chemical class of biologically active diterpene acids related to PLAB may have promise for the treatment of metabolic and pathophysiological disorders that are regulated by these nuclear receptor isoforms.

References

• 1 Walsh T J. Invasive fungal infections: problems and challenges for developing new antifungal compounds. In: Sutcliffe JA, Georgopapadakou NH, editors Emerging Targets in antimicrobial and antifungal infections. Chapman and Hall New York; 1992: p. 349-73
  Google Scholar
• 2 Li E, Clark A, Hufford C. Antifungal evaluation of pseudolaric acid B, a major constitute of Pseudolarix kaempferi .  Journal of Natural Products. 1995;  58 57-67
  CrossrefPubMedGoogle Scholar
• 3 Pan D-Q, Li Z-L, Hu C-Q, Chen K, Chang J-J, Lee K-H. The cytotoxic principles of Pseudolarix kaempferi; Pseudolaric acid-A and -B and related derivatives.  Planta Medica. 1990;  56 383-5
  PubMedGoogle Scholar
• 4 Escher P, Wahli W. Peroxisome proliferator-activated receptors: insight into multiple cellular functions.  Mutation Research. 2000;  448 121-38
  PubMedGoogle Scholar
• 5 Vamecq J, Latruffe N. Medical significance of peroxisome proliferator-activated receptors.  The Lancet. 1999;  354 141-8
  CrossrefPubMedGoogle Scholar
• 6 Willson T M, Brown P J, Sternbach D D, Henke B R. The PPARs: From orphan receptors to drug discovery.  Journal of Medicinal Chemistry. 2000;  43 527-50
  CrossrefPubMedGoogle Scholar
• 7 Ohtomo R, Kobayashi K, Muraoka S, Ohkuma M, Ohta A, Takagi M. Peroxisome proliferators activate cytochrome P450 genes in an alkane assimilating yeast, Candida maltosa .  Biochemical and Biopyhsical Research Communications. 1996;  222 790-3
  PubMedGoogle Scholar
• 8 Sheridan R, Ratledge C. Changes in cell morphology and carnitine acetyltransferase activity in Candida albicans follow growth on lipids and serum and after in vivo incubation in mice.  Microbiology. 1996;  142 3171-80
  PubMedGoogle Scholar
• 9 Weyer U, Schafer R, Himmler A, Mayer S K, Burger E, Czernilofsky A P, Stratowa C. Establishment of a cellular assay system for G protein linked receptor: Coupling of human NK2 and 5-HT2 receptors to phospholipase C activates a luciferase reporter gene.  Receptors and Channels. 1993;  1 193-200
  PubMedGoogle Scholar
• 10 Mukherjee R, Jow L, Noonan, McDonnell D P. Human and rat peroxisome proliferator activated receptors (PPARs) demonstrate similar tissue distribution but different responsiveness to PPAR activators.  Steroid Biochemistry and Molecular Biology. 1994;  51 157-66
  PubMedGoogle Scholar
• 11 Henry K, O'Brien M L, Clevenger W, Jow L, Noonan D J. Peroxisome proliferator-activated receptor response specificities as defined in yeast and mammalian cell transcription assays.  Toxicology and Applied Pharmacology. 1995;  132 317-24
  CrossrefPubMedGoogle Scholar
• 12 Rangwala S M, O'Brien M L, Loiodice F, Longo A, Tortorella V, Noonan D J, Feller D R. Stereoselective effects of chiral clofibric acid analogs on rat peroxisome proliferator-activated receptor alpha activation and peroxisome fatty acid β-oxidation.  Chirality. 1997;  9 37-47
  CrossrefPubMedGoogle Scholar
• 13 Osumi T, Wen J, Hashimoto T. Two cis-acting regulatory sequences in the peroxisome proliferator-responsive enhancer region of the rat acyl-CoA oxidase gene.  Biochemical and Biophysical Research Communications. 1991;  175 866-71
  CrossrefPubMedGoogle Scholar
• 14 Yuan X. Characterization of rat peroxisome proliferator-activated receptors and their cross-talk with insulin and okadaic acid-mediated signaling pathways. Ph.D. Dissertation 2000, Department of Biochemistry, University of Kentucky Lexington, KY, USA;
  Google Scholar
• 15 Sambrook J, Fritsch E F, Maniatis T. In: Molecular Cloning, A Laboratory Manual, second edition. Book 2, Chapter 10, Preparation of Radiolabeled DNA and RNA Probes. Cold Spring Harbor, NY Cold Spring Harbor Press 1989: Part 10.51
  Google Scholar
• 16 Schmidt A, Endo N, Rutledge S J, Vogel R, Shinar D, Rodan G A. Identification of a new member of the steroid receptor superfamily that is activated by a peroxisome proliferator and fatty acids.  Molecular Endocrinology. 1992;  6 1634-41
  CrossrefPubMedGoogle Scholar
• 17 Giguere V, Hollenberg S, Rosenfeld M, Evans R M. Functional domains of the human glucocorticoid receptor.  Cell. 1986;  46 645-52
  CrossrefPubMedGoogle Scholar
• 18 Walusimbi-Kisitu M, Harrison E H. Fluorometric assay for rat liver peroxisomal fatty acyl-coenzyme A oxidase activity.  Journal of Lipid Research. 1983;  24 1077-84
  PubMedGoogle Scholar
• 19 Kliewer S A, Forman B M, Blumberg B, Ong E S, Borgmeyer U, Mangelsdorf D J, Umesono K, Evans R M. Differential expression and activation of a family of murine peroxisome proliferator-activated receptors.  Proceedings of the National Academy of Sciences (USA). 1994;  91 7355-9
  PubMedGoogle Scholar
• 20 Shalev A, Siegrist-Kaiser C E, Yen P M. The peroxisome proliferator-activated receptor is a phosphoprotein: regulation by insulin.  Endocrinology. 1996;  137 4499-502
  CrossrefPubMedGoogle Scholar
• 21 Feller D R, Jaradat M S, Nagmani N, Wu B, Avery M A. Pseudolaric acid analogs as activators of peroxisome proliferator-activated receptor isoforms. Experimental Biology Meeting, Abstract LB 219 March 31 - April 4, 2001 Orlando, Fl;
  Google Scholar

Prof. Dennis R. Feller

Department of Pharmacology

University of Mississippi 303


Faser Hall Post Office Box 1848

University MS 38677-1848

USA

Email: dfeller@olemiss.edu

Phone: +1-662-915-7330

Fax: +1-662-915-5148