Ginkgotoxin

Ginkgotoxin
Names
Preferred IUPAC name
5-(Hydroxymethyl)-4-(methoxymethyl)-2-methylpyridin-3-ol
Other names
4'-O-methylpyridoxine; 4-O-methylpyridoxine
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
  • InChI=1S/C9H13NO3/c1-6-9(12)8(5-13-2)7(4-11)3-10-6/h3,11-12H,4-5H2,1-2H3 checkY
    Key: SVINQHQHARVZFF-UHFFFAOYSA-N checkY
  • Oc1c(c(cnc1C)CO)COC
Properties
C9H13NO3
Molar mass 183.207 g·mol−1
Hazards
GHS labelling:
GHS06: Toxic
Danger
H300, H330
P260, P264, P270, P271, P284, P301+P310, P304+P340, P310, P320, P321, P330, P403+P233, P405, P501
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
☒N verify (what is checkY☒N ?)

Ginkgotoxin (4'-O-methylpyridoxine) is a neurotoxin naturally occurring in Ginkgo biloba. It is an antivitamin structurally related to vitamin B6 (pyridoxine). It has the capacity to induce epileptic seizures.

Occurrence

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Seeds and phytopharmaceuticals derived from the plant Ginkgo biloba are dietary supplements used to improve memory,[1] brain metabolism,[2] and blood flow,[3] and to treat neuronal disorders.[4][5] It has been long used for a wide range of medicinal purposes. For instance, in Japan and China, Ginkgo biloba is used to treat cough, bronchial asthma, irritable bladder and alcohol use disorder.[6]

Ginkgotoxin is found in the seeds and, in lesser amounts, in the leaves of Ginkgo biloba. The seeds can be consumed as is and the leaves can be used to prepare the dietary supplements. Analyses of raw seeds from eight different locations in Japan by high-performance liquid chromatography showed concentrations of ginkgotoxin varying from 0.173 to 0.4 mg/g of seeds.[7] Also, there is a seasonal variation of ginkgotoxin concentration in the seeds. The maximum has been observed in August.[8] Analyses of the powder of Ginkgo biloba capsules revealed the presence of ginkgotoxin. However, as most oral supplements are made from the leaves, which contain only small amounts of ginkgotoxin,[9] below the level of toxicological relevance.[10]

Ginkgotoxin-5'-glucoside is a derivative of ginkgotoxin that possesses a glycosyl in the 5' position. Its content is higher than the concentration of ginkgotoxin in heated seeds (boiled or roasted).[11] Liberation of ginkgotoxin by enzymatic hydrolysis of the glycosidic linkage is possible. Nevertheless, the toxicity or the mechanism of action of the glucoside form is not fully understood.

Ginkgotoxin can also be found in plants of the genus Albizia.[8] However, these plants have no known dietary use for humans, so their production of ginkgotoxin is of lesser concern.

Biosynthesis

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Ginkgotoxin is the 4'-O-methyl derivative of vitamin B6 (pyridoxine), but the presence of the vitamin is not required for the biosynthesis of ginkgotoxin. It indicates that the pyridoxine system can be synthesized de novo in the cells of Ginkgo biloba.[12]

Biosynthesis of ginkgotoxin

The first step of the biosynthesis involves ribulose 5-phosphate and dihydroxyacetone phosphate. They react in the presence of a synthase complex consisting of Pdx1 and Pdx2, and form pyridoxal phosphate. The second step is hypothetical and consists of the removal of a hydride in the presence of a dehydrogenase to produce pyridoxine. The last step involves the O-methylation of pyridoxine to form 4'-O-methylpyridoxine (ginkgotoxin).[6]

Toxicity

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A few cases reported poisoning from commercially available products. The consumption of seeds represent a greater concern. Overconsumption of Ginkgo biloba seeds, especially by children, can result in loss of consciousness, convulsions, and death.[11]

Ginkgotoxin is structurally related to vitamin B6. It is suspected that ginkgotoxin interferes with the synthesis of the vitamin by decreasing the activity of pyridoxal kinase in mammals.[13] This decrease leads to the decreased availability of glutamate decarboxylase. In turn, it causes an imbalance between excitation and inhibition of neurotransmitters, resulting in epileptic seizures.[13] The toxicity of ginkgotoxin consequently can be relieved by taking vitamin B6 supplements.

References

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  1. ^ Liu, Haolong; Ye, Min; Guo, Hongzhu (2020-02-21). "An Updated Review of Randomized Clinical Trials Testing the Improvement of Cognitive Function of Ginkgo biloba Extract in Healthy People and Alzheimer's Patients". Frontiers in Pharmacology. 10. doi:10.3389/fphar.2019.01688. ISSN 1663-9812. PMC 7047126. PMID 32153388.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  2. ^ Xu, Lili; Hu, Zhiyong; Shen, Jianjun; McQuillan, Patrick M. (2015). "Effects of Ginkgo biloba extract on cerebral oxygen and glucose metabolism in elderly patients with pre-existing cerebral ischemia". Complementary Therapies in Medicine. 23 (2): 220–225. doi:10.1016/j.ctim.2014.12.009.
  3. ^ Pittler, Max H; Ernst, Edzard (2000). "Ginkgo Biloba extract for the treatment of intermittent claudication: a meta-analysis of randomized trials". The American Journal of Medicine. 108 (4): 276–281. doi:10.1016/S0002-9343(99)00454-4.
  4. ^ Weinmann, Stefan; Roll, Stephanie; Schwarzbach, Christoph; Vauth, Christoph; Willich, Stefan N (2010). "Effects of Ginkgo biloba in dementia: systematic review and meta-analysis". BMC Geriatrics. 10 (1). doi:10.1186/1471-2318-10-14. ISSN 1471-2318. PMC 2846949. PMID 20236541.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  5. ^ Barbalho, Sandra Maria; Direito, Rosa; Laurindo, Lucas Fornari; Marton, Ledyane Taynara; Guiguer, Elen Landgraf; Goulart, Ricardo de Alvares; Tofano, Ricardo José; Carvalho, Antonely C. A.; Flato, Uri Adrian Prync; Capelluppi Tofano, Viviane Alessandra; Detregiachi, Cláudia Rucco Penteado; Bueno, Patrícia C. Santos; Girio, Raul S. J.; Araújo, Adriano Cressoni (2022-03-09). "Ginkgo biloba in the Aging Process: A Narrative Review". Antioxidants. 11 (3): 525. doi:10.3390/antiox11030525. ISSN 2076-3921. PMC 8944638. PMID 35326176.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  6. ^ a b Leistner E.; Drewke C. (2010). "Ginkgo biloba and ginkgotoxin". Journal of Natural Products. 73 (1): 86–92. doi:10.1021/np9005019. PMID 20041670.
  7. ^ Van Beek T.A.; Montoro P. (2009). "Chemical analysis and quality control of Ginkgo biloba leaves, extracts, and phytopharmaceuticals". Journal of Chromatography A. 1216 (11): 2002–2032. doi:10.1016/j.chroma.2009.01.013. PMID 19195661.
  8. ^ a b Scott P.M.; Lau B.Y-P.; Lawrence G.A.; Lewis D.A. (2000). "Analysis of Ginkgo biloba for the presence of ginkgotoxin and ginkgotoxin-5'-glucoside". Journal of AOAC International. 83 (6): 1313–1320. doi:10.1093/jaoac/83.6.1313. PMID 11128132.
  9. ^ Leistner, Eckhard; Drewke, Christel (2010-01-22). "Ginkgo biloba and Ginkgotoxin". Journal of Natural Products. 73 (1): 86–92. doi:10.1021/np9005019. ISSN 0163-3864.
  10. ^ Mei, Nan; Guo, Xiaoqing; Ren, Zhen; Kobayashi, Daisuke; Wada, Keiji; Guo, Lei (2017-01-02). "Review of Ginkgo biloba -induced toxicity, from experimental studies to human case reports". Journal of Environmental Science and Health, Part C. 35 (1): 1–28. doi:10.1080/10590501.2016.1278298. ISSN 1059-0501. PMC 6373469. PMID 28055331.
  11. ^ a b Yoshimura T.; Udaka N.; Morita J.; Jinyu Z.; Sazaki K.; Kobayashi D.; Wada K. (2006). "High performance liquid chromatographic determination of ginkgotoxin and ginkgotoxin-5'-glucoside in Ginkgo biloba seeds". Journal of Liquid Chromatography & Related Technologies. 29 (4): 605–616. doi:10.1080/10826070500531466.
  12. ^ Fiehe K.; Arenz A.; Drewke C.; Hemscheidt T.; Williamson R.T.; Leistner E. (2000). "Biosynthesis of 4'-O-methylpyridoxine (ginkgotoxin) from primary precursors". Journal of Natural Products. 63 (2): 185–189. doi:10.1021/np990414+. PMID 10691705.
  13. ^ a b Kästner U.; Hallmen C.; Wiese M.; Leistner E.; Drewke C. (2007). "The human pyridoxal kinase, a plausible target for ginkgotoxin from Ginkgo biloba". The FEBS Journal. 274 (4): 1036–1045. doi:10.1111/j.1742-4658.2007.05654.x. PMID 17250738.
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