Planta Med 2009; 75(6): 563-567
DOI: 10.1055/s-0029-1185482
Rapid Communication
Original Paper
© Georg Thieme Verlag KG Stuttgart · New York

Influence of Antivitamins Ginkgotoxin 5′-Phosphate and Deoxypyridoxine 5′-Phosphate on Human Pyridoxine 5′-Phosphate Oxidase[*]

Nora Salamon1 , Cristian Gurgui1 , Eckhard Leistner1 , Christel Drewke1
  • 1Institute of Pharmaceutical Biology, University of Bonn, Bonn, Germany
Further Information

Publication History

received Dec. 18, 2008 revised January 28, 2009

accepted February 12, 2009

Publication Date:
13 March 2009 (online)

Abstract

The pharmacological effects of leaf extracts (EGb 761) from Ginkgo biloba L. are attributed to ginkgolides, bilobalide and biflavonoids. However, besides these beneficial attributes, ginkgotoxin, a B6 antivitamin which may cause epileptic convulsions, other severe neuronal disorders and even death, is also found in Ginkgo leaves and leaf-derived remedies. Because of its structural similarity to the B6 vitamers, an interaction of ginkgotoxin with enzymes involved in the vitamin B6-dependent metabolism of the human brain is possible. This led us to investigate how the neurotoxic ginkgotoxin acts in the brain. To this end the gene coding for the human pyridoxine 5′-phosphate oxidase was heterologously overexpressed in E. coli and the homogeneous enzyme was characterized. The investigation showed that the enzyme is inhibited in vitro by the synthetic vitamin B6 derivative 4′-deoxypyridoxine 5′-phosphate but not by ginkgotoxin or its 5′-phosphate.

1 Dedicated to Dr. Heinz G. Floss on the occasion of his 75th birthday.

References

  • 1 Oberpichler-Schwenk H, Krieglstein J. Pharmakologische Wirkungen von Ginkgo biloba-Extrakt und – Inhaltsstoffen.  Pharm Unserer Zeit. 1992;  21 224-235
  • 2 Tang W, Eisenbrand G. Chinese drugs of plant origin. Chemistry, pharmacology, and use in traditional and modern medicine. Berlin; Springer Verlag 1992: 555-565
  • 3 Okabe K, Yamada S, Yanamura S, Takada S. Ginkgolides.  J Chem Soc (London). 1967;  C 2201-2206
  • 4 van Beek Z A, Lelyveld G P. Concentration of ginkgolides and bilobalide in Ginkgo biloba leaves in relation to the time of the year.  Planta Med. 1992;  58 413-416
  • 5 Briancon-Scheid F, Lobstein-Guth A, Anton R. HPLC separation and quantitative determination of biflavones in leaves from Ginkgo biloba.  Planta Med. 1983;  49 204-207
  • 6 Arenz A, Klein M, Fiehe K, Groß J, Drewke C, Hemscheidt T, Leistner E. Occurrence of neurotoxic 4′-O- methylpyridoxine in Ginkgo biloba leaves, Ginkgo medications and Japanese Ginkgo food.  Planta Med. 1996;  62 548-551
  • 7 Nitsch C, Okada Y. Differential decrease of GABA in the substantia nigra and other discrete regions of the rabbit brain during the preictal period of methoxypyridoxine-induced seizures.  Brain Res. 1976;  105 173-178
  • 8 Nitsch C. Regulation of GABA metabolism in discrete rabbit brain regions under methoxypyridoxine – regional differences in cofactor saturation and the preictal activation of glutamate decarboxylase activity.  J Neurochem. 1980;  34 822-830
  • 9 Haug P, Nitsch C. Increase in taurine content before onset of seizures induced by a glutamate decarboxylase inhibitor.  Exp Brain Res. 1982;  48 463-466
  • 10 Wada K, Haga M. Food poisoning by Ginkgo biloba seeds. Hori T, Ridge RW, Tulecke W, Del Tredici P, Tremouillaux-Guiller J, Tobe H Ginkgo biloba – a global treasure, from biology to medicine. Tokyo; Springer Verlag 1997: 309-321
  • 11 Mizuno N, Kawakami K, Morita E J. Competitive inhibition between 4′-substituted pyridoxine analogues and pyridoxal for pyridoxal kinase from mouse brain.  J Nutr Sci Vitaminol. 1980;  26 535-543
  • 12 Yanai A, Minami M, Takano Y, Endo T, Hamaue M, Wada K, Take Y, Haga M, Morii K, Togashi H, Yoshioka M, Saito H. 4′-O-methylpyridoxine-induced convulsion in guinea pigs and rats.  Life Sci Adv. 1990;  107 1499-1500
  • 13 Wada K, Ishigaki S, Ueda K, Sakata M, Haga M. An antivitamin B6, 4′-methoxypyridoxine, from the seed of Ginkgo biloba L.  Chem Pharm Bull (Tokyo). 1985;  33 3555-3557
  • 14 Wada K. Ginkgo seeds food poisoning.  Chudoku Kenkyu. 2005;  18 11-16
  • 15 Buss K, Drewke C, Lohmann S, Piwonska A, Leistner E. Properties and interaction of heterologously expressed glutamate decarboxylase isoenzymes GAD (65 kDa) and GAD (67 kDa) from human brain with ginkgotoxin and its 5′-phosphate.  J Med Chem. 2001;  44 3166-3174
  • 16 Yagi M, Wada K, Sakata M, Kokubo M, Haga M. Studies on the constituents of edible and medicinal plants, IV, determination of 4′-O-methylpyridoxine in serum of the patient with Gin-nan food poisoning.  Yakugaku Zasshi. 1993;  113 596-599
  • 17 Hori Y, Fujisawa M, Shimada K, Oda A, Katsuyama S, Wada K. Rapid analysis of 4′-O-methylpyridoxine in the serum of patients with Ginkgo biloba seed poisoning by ion-pair high-performance liquid chromatography.  Biol Pharm Bull. 2004;  27 486-491
  • 18 Kästner U, Hallmen C, Wiese M, Leistner E, Drewke C. The human pyridoxal kinase, a plausible target for ginkgotoxin from Ginkgo biloba.  FEBS J. 2007;  274 1036-1045
  • 19 Cho S Y, Churchich J E, Zaiden E, Kwok F. Brain pyridoxine 5-phosphate oxidase. Modulation of its catalytic activity by reaction with pyridoxal 5′-phosphate and analogs.  J Biol Chem. 1987;  262 12013-12017
  • 20 Notheis C, Drewke C, Leistner E. Purification and characterization of the pyridoxol 5′-phosphate: oxygen oxidoreductase (deaminating) from Escherichia coli. .  Biochim Biophys Acta. 1995;  1247 265-271
  • 21 Wada H, Snell E. The enzymatic oxidation of pyridoxine and pyridoxamine phosphates.  J Biol Chem. 1961;  236 2089-2095
  • 22 Laemmli U K. Cleavage of structural proteins during the assembly of the head of bacteriophage T4.  Nature. 1970;  227 680-685
  • 23 Cash C D, Maitre M, Rumigny J F, Mandel P. Rapid purification by affinity chromatography of rat brain pyridoxal kinase and pyridoxamine-5-phosphate oxidase.  Biochem Biophys Res Commun. 1980;  96 1755-1760
  • 24 Bahn J H, Kwon O S, Joo H M, Ho Jang S, Park J, Hwang I K, Kang T C, Won M H, Yil Kwon H, Kwok F, Kim H B, Cho S W, Choi S Y. Immunohistochemical studies of brain pyridoxine-5′-phosphate oxidase.  Brain Res. 2002;  925 159-168
  • 25 Kazarinoff M N, McCormick D B. Rabbit liver pyridoxamine (pyridoxine) 5′-phosphate oxidase. Purification and properties.  J Biol Chem. 1975;  250 3436-3442
  • 26 Zhao G, Winkler M E. Kinetic limitation and cellular amount of pyridoxine (pyridoxamine) 5′-phosphate oxidase of Escherichia coli K‐12.  J Bacteriol. 1995;  177 883-891
  • 27 Jang Y M, Kim D W, Kang T C, Won M H, Baek N I, Moon B J, Choi S Y, Kwon O S. Human pyridoxal phosphatase: molecular cloning, functional expression and tissue distribution.  J Biol Chem. 2003;  278 50040-50046
  • 28 Granger A S. Ginkgo biloba precipitationg epileptic seizures.  Age Aging. 2001;  3 523-525
  • 29 Gregory P J. Seizures associated with Ginkgo biloba?.  Ann Intern Med. 2001;  134 344
  • 30 Ivetic V, Popovic M, Naumovic N, Radenkovic M, Vasic V. The effect of Ginkgo biloba (EGb 761) on epileptic activity in rabbits.  Molecules. 2008;  13 2509-2520

1 Dedicated to Dr. Heinz G. Floss on the occasion of his 75th birthday.

Dr. C. Drewke

Institute of Pharmaceutical Biology
University of Bonn

Nussallee 6

53115 Bonn

Germany

Phone: + 49 2 28 73 25 63

Fax: + 49 2 28 73 32 50

Email: cdrewke@uni-bonn.de