Planta Med 2000; 66(8): 753-756
DOI: 10.1055/s-2000-9781
Letter
© Georg Thieme Verlag Stuttgart · New York

Galloyl Esters from Rhubarb are Potent Inhibitors of Squalene Epoxidase, a Key Enzyme in Cholesterol Biosynthesis

Ikuro Abe1,*, Takahiro Seki1 , Hiroshi Noguchi1 , Yoshiki Kashiwada2
  • 1 University of Shizuoka, School of Pharmaceutical Sciences, Shizuoka, Japan
  • 2 Niigata College of Pharmacy, Niigata, Japan
Further Information

Publication History

Publication Date:
31 December 2000 (online)

Abstract

Galloyl glucoses and galloyl proanthocyanidins obtained from rhubarb (Rhei Rhizoma, Rheum palmatum L., Polygonaceae); e.g. 1,2,6-tri-O-galloyl-β-D-glucose (IC50 = 0.63 μM), 1,6-di-O-galloyl-2-O-cinnamoyl-β-D-glucose (IC50 = 0.58 μM), procyanidin B-2 3,3′-di-O-gallate (IC50 = 0.54 μM), and procyanidin B-5 3,3′-di-O-gallate (IC50 = 0.55 μM), were found to be potent inhibitors of rat squalene epoxidase (SE). The inhibition at submicromolar level was far more potent than that of chemically synthesized substrate analogs. It was demonstrated for the first time that the cholesterol-lowering effect of rhubarb may be attributed to the potent inhibition activities of SE, a rate-limiting enzyme of cholesterol biogenesis.

References

  • 1 Abe  I,, Prestwich  G D.. Squalene epoxidase and oxidosqualene: Lanosterol cyclase. Comprehensive natural products chemistry, 2.10,. In: Barton DHR, Nakanishi K, editors Vol. 2. Oxford:; Pergamon, 1999: 267-98
  • 2 Sakakibara  J,, Watanabe  R,, Kanai  Y,, Ono  T.. Molecular cloning and expression of rat squalene epoxidase.  J. Biol. Chem.. 1995;;  270 17-20
  • 3 Nakamura  P,, Sakakibara  J,, Izumi  T,, Shibata  A,, Ono  T.. Transcriptional regulation of squalene epoxidase by sterols and inhibitors in Hela cells.  J. Biol. Chem.. 1996;;  271 8053-6
  • 4 Nagumo  A,, Kamei  T,, Sakakibara  J,, Ono  T.. Purification and characterization of recombinant squalene epoxidase.  J. Lipid Res.. 1995;;  36 1489-97
  • 5 Abe  I,, Tomesch  J C,, Wattanasin  S,, Prestwich  G D.. Inhibitors of squalene biosynthesis and metabolism.  Nat. Prod. Rep.. 1994;;  11 279-302
  • 6 Abe  I,, Prestwich  G D.. Development of new cholesterol-lowering drugs: Inhibitors of squalene biosynthesis and metabolism.  Drug Discovery Today. 1998;;  3 389-90
  • 7 Abe  I,, Seki  T,, Umehara  K,, Miyase  T,, Noguchi  H,, Sakakibara  J,, Ono  T.. Green tea polyphenols: Novel and potent inhibitors of squalene epoxidase.  Biochem. Biophys. Res. Commun.. 2000;;  268 767-71
  • 8 Aonuma  S,, Mimura  T,, Tarutani  M.. Effects of Coptis, Scutellaria, rhubarb, and Bupleurum on the serum cholesterol and phospholipid of rabbits.  Yakugaku Zasshi. 1957;;  77 1303-7
  • 9 Muramatsu  K,, Fukuyo  M,, Hara  Y.. Effect of green tea catechins on plasma cholesterol level in cholesterol-fed rats.  J. Nutr. Sci. Vitaminol.. 1986;;  32 613-22
  • 10 Fukuyo  M,, Hara  Y,, Muramatsu  K.. Effect of tea leaf catechin, (-)-epigallocatechin gallate, on plasma cholesterol level in rat.  J. Jpn. Soc. Nutr. Food Sci.. 1986;;  39 495-500
  • 11 Yamahara  J,, Sawada  T,, Fujimura  H.. Experimental atherosclerosis in mice fed a butter-rich diet and effect of Kanpo-prescriptions and crude drugs on this model.  Proc. Symp. WAKAN-YAKU. 1983;;  16 167-70
  • 12 Nonaka  G,, Nishioka  I,, Nagasawa  T,, Oura  H.. Tannins and related compounds. I. Rhubarb (1).  Chem. Pharm. Bull.. 1981;;  29 2862-70
  • 13 Kashiwada  Y,, Nonaka  G,, Nishioka  I.. Tannins and related compounds. XLVII. Rhubarb (6). Isolation and characterization of new p-hydroxyphenylbutanones, stilbenes and gallic acid glucosides.  Chem. Pharm. Bull.. 1986;;  34 3237-43
  • 14 Kashiwada  Y,, Nonaka  G,, Nishioka  I,, Nishizawa  M,, Yamagishi  T.. Studies on rhubarb (Rhei Rhizoma). XIV. Isolation and characterization of stilbene glucosides from Chinese rhubarb.  Chem. Pharm. Bull.. 1988;;  36 1545-9
  • 15 Sen  S E,, Prestwich  G D.. Trisnorsqualene alcohol, a potent inhibitor of vertebrate squalene epoxidase.  J. Am. Chem. Soc.. 1989;;  111 1508-10
  • 16 Sen  S E,, Prestwich  G D.. Trisnorsqualene cyclopropylamine: a reversible, tight-binding inhibitor of squalene epoxidase.  J. Am. Chem. Soc.. 1989;;  111 8761-2
  • 17 Moore  W R,, Schatzman  G L,, Jarvi  E T,, Gross  R S,, McCarthy  J R.. Terminal difluoro olefin analogues of squalene are time-dependent inhibitors of squalene epoxidase.  J. Am. Chem. Soc.. 1992;;  114 360-1
  • 18 Horie  M,, Tsuchiya  Y,, Hayashi  M,, Iida  Y,, Iwasawa  Y,, Nagata  Y,, Sawasaki  Y,, Fukuzumi  H,, Kitani  K,, Kamei  T.. NB-598: a potent competitive inhibitor of squalene epoxidase.  J. Biol. Chem.. 1990;;  265 18075-8
  • 19 Nonaka  G,, Muta  M,, Nishioka  I.. Myricatin, a galloyl flavanol sulfate and prodelphinidin gallates from Myrica rubra.  Phytochemistry. 1983;;  22 237-41
  • 20 Jovanovic  S V,, Hara  Y,, Steenken  S,, Simic  M G.. Antioxidant potential of gallocatechins. A pulse radiolysis and laser photolysis study.  J. Am. Chem. Soc.. 1995;;  117 9881-8

Dr. Ikuro Abe

University of Shizuoka School of Pharmaceutical Sciences

52-1 Yada

Shizuoka 422-8526

Japan

Email: abei@ys7.u-shizuoka-ken-ac.jp

Phone: +81-54-264-5662