Planta Med 2002; 68(8): 676-679
DOI: 10.1055/s-2002-33801
Original Paper
Pharmacology
© Georg Thieme Verlag Stuttgart · New York

Physiological Responses to a Natural Antioxidant Flavonoid Mixture, Silymarin, in BALB/c Mice: I Induction of Transforming Growth Factor β1 and c-myc in Liver with Marginal Effects on Other Genes

Quanren He1 , Marcin F. Osuchowski1, 2 , Victor J. Johnson1 , Raghubir P. Sharma1
  • 1Department of Physiology and Pharmacology, College of Veterinary Medicine, The University of Georgia, Athens, GA, USA
  • 2Department of Animal Anatomy, Faculty of Veterinary Medicine, University Warmia and Mazury, Olsztyn, Poland
Further Information

Publication History

Received: November 30, 2001

Accepted: February 23, 2002

Publication Date:
09 September 2002 (online)

Abstract

Silymarin, a mixture of flavonolignans isolated from Silybum marianum, is known for its hepatoprotective properties. We investigated the expression of cytokines in mouse liver following treatment with 0, 10, 50, and 250 mg/kg of silymarin once daily for 5 days. A dose-related but insignificant decrease of circulating alanine aminotransferase and aspartate aminotransferase after silymarin treatment was observed, suggesting that silymarin treatment did not induce hepatic damage. Silymarin treatment caused significant increases in the expressions of transforming growth factor (TGF) β1 and c-myc in liver. No significant difference was detected among these treatments in the expression of hepatocyte growth factor, interferon γ, tumor necrosis factor α, and class II major histocompatibility complex. These results suggest that alterations of TGFβ1 and c-myc expression in the liver may be involved in the hepatoprotective effects of silymarin observed in other studies.

References

  • 1 Flora K, Hahn M, Rosen H, Benner K. Milk thistle (Silybum marianum) for the therapy of liver disease.  Am J Gastroenterol. 1998;  93 149-53
  • 2 Sonnenbichler J, Scalera F, Sonnebichler I, Weyhenmeyer R. Stimulatory effects of silibinin and silicristin from the milk thistle Silybum marianum on kidney cells.  J Pharmacol Exp Ther. 1999;  290 1475-89
  • 3 Zi X, Mukhtar H, Agarwal R. Novel cancer chemopreventive effects of a flavonoid antioxidant silymarin: Inhibition of mRNA expression of an endogenous tumor promoter TNFα.  Biochem Biophy Res Commun. 1997;  239 334-9
  • 4 Puerta De La R, Martinez E, Bravo L, Ahumada M C. Effect of silymarin on different acute inflammation models and on leukocyte migration.  J Pharm Pharmacol. 1996;  48 968-70
  • 5 Agarwal R. Cell signaling and regulators of cell cycle as molecular targets for prostate cancer prevention by dietary agents.  Biochem Pharmacol. 2000;  60 1051-9
  • 6 Zi X, Zhang J, Agarwal R, Pollak M. Silibinin up-regulates insulin-like growth factor-binding protein 3 expression and inhibits proliferation of androgen-independent prostate cancer cells.  Cancer Res. 2000;  60 5618-20
  • 7 Cho J Y, Kim P S, Park J, Yoo E S, Baik K U, Kim Y-K, Park M H. Inhibitor of tumor necrosis factor-α production in lipopolysaccharide-stimulated RAW264.7 cells from Amorpha fruticosa .  J Ethnopharmacol. 2000;  70 137-43
  • 8 Raso G M, Meli R, Carlo G D, Pacilio M, Carlo R D. Inhibition of inducible nitric oxide synthase and cycloxygenase-2 expression by flavonoids in macrophage J774A.1 cells.  Life Sci. 2001;  68 921-31
  • 9 Neuman M G, Cameron R G, Haber J A, Katz G G, Malkiewicz I M, Shear N H. Inducers of cytochrome P450 2E1 enhance methotrexate-induced hepatocytotoxicity.  Clin Biochem. 1999;  32 519-36
  • 10 Sharma R P, Bhandari N, Riley R T, Voss K A, Meredith F I. Tolerance to fumonisin toxicity in a mouse strain lacking the P75 tumor necrosis factor receptor.  Toxicology. 2000;  153 183-94
  • 11 De Bless P J, Niki T, Rogiers V, Geerts A. Transforming growth factor-beta gene expression in normal and fibrotic rat liver.  J Hepatol. 1997;  26 886-93
  • 12 Flisiak R, Pytel-Krolczuk B, Prokopowicz D. Circulating transforming growth factor β1 as an indicator of hepatic function impairment in liver cirrhosis.  Cytokine. 2000;  13 677-81
  • 13 Kanzler S, Lohse A W, Keil A, Henninger J, Dienes H, Schirmacher P, Rose-John S, Meyer zum Büschenfelde K H, Blessing M. TGF-β1 in liver fibrosis: an inducible transgenic mouse model to study liver fibrogenesis.  Am J Physiol. 1999;  276 G1059-68
  • 14 Bedossa P, Paradis V. Transforming growth factor-beta (TGF-beta): a key-role in liver fibrogenesis.  J Hepatol. 1995;  22 (Suppl. 2) 37-42
  • 15 Warner B J, Blain S W, Seoane J, Massagué J. Myc downregulation by transforming growth factor β required for activation of the p15Ink4b G1 arrest pathway.  Mol Cell Biol. 1999;  19 5914-22
  • 16 Alexandrow M, Moses H L. Transforming growth factor β and cell cycle regulation.  Cancer Res. 1996;  55 1552-7
  • 17 Claassen G F, Hann S R. A role for transcriptional repression of p21Cip1 by c-Myc in overcoming transforming factor β-induced cell-cycle arrest.  Proc Natl Acad Sci USA. 2000;  97 9498-503
  • 18 Dong Y, Tang L, Letterio J J, Benveniste E N. The Smad3 protein is involved in TGF-β inhibition of class II transactivation and class II MHC expression.  J Immunol. 2001;  167 311-9
  • 19 Conzen S D, Gottlob K, Kandel E, Khanduri P, Wagner A J, O'leary M, Hay N. Induction of cell cycle progression and acceleration of apoptosis are two separable functions of c-Myc: transrepression correlates with acceleration of apoptosis.  Mol Cell Biol. 2000;  20 6008-108

Dr. Raghubir P. Sharma

Department of Physiology and Pharmacology

College of Veterinary Medicine


The University of Georgia

Athens, GA 30602-7389, U.S.A.

Phone: +1-706-542-2788

Fax: +1-706-542-3015

Email: rpsharma@vet.uga.edu

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