Berberine

Berberine is a quaternary ammonium salt from the protoberberine group of benzylisoquinoline alkaloids found in such plants as Berberis (e.g. Berberis vulgaris – barberry, Berberis aristata – tree turmeric, Mahonia aquifolium – Oregon-grape, Hydrastis canadensis – goldenseal, Xanthorhiza simplicissima – yellowroot, Phellodendron amurense[2] – Amur cork tree, Coptis chinensis – Chinese goldthread, Tinospora cordifolia, Argemone mexicana – prickly poppy, and Eschscholzia californica – Californian poppy). Berberine is usually found in the roots, rhizomes, stems, and bark.

Due to berberine’s strong yellow color, Berberis species were used to dye wool, leather, and wood. Wool is still dyed with berberine today in northern India.[3] Under ultraviolet light, berberine shows a strong yellow fluorescence,[4] so it is useful in histology for staining heparin in mast cells.[5]

Research

Berberine was supposedly used in China as a folk medicine by Shennong around 3000 BC. This first recorded use of berberine is described in the ancient Chinese medical book The Divine Farmer’s Herb-Root Classic.[6]

Berberine is under investigation to determine whether it may have applications for treating arrhythmia, diabetes,[7] hyperlipidemia,[8] inflammation[9]and cancer. Berberine exerts class III antiarrhythmic action.[10] There is some evidence that berberine may have anti-aging (gero-suppressive) properties.[11][12] In live cells, berberine localizes in mitochondria. Its mitochondrial localization is consistent with inhibition of complex I of respiratory chain, decrease of ATP production, and subsequent activation of AMPK, which leads to suppression of mTOR signaling.[11] The bioavailability of berberine is low.[13]

Some research has been undertaken into possible use against methicillin-resistant Staphylococcus aureus (MRSA) infection.[14] Berberine is considered antibiotic.[15][16] When applied in vitro and in combination with methoxyhydnocarpin, an inhibitor of multidrug resistance pumps, berberine inhibits growth of Staphylococcus aureus[17] and Microcystis aeruginosa,[18] a toxic cyanobacterium.

Biosynthesis of berberine

The alkaloid berberine has a tetracyclic skeleton derived from a benzyltetrahydroisoquinoline system with the incorporation of an extra carbon atom provided by S-adenosyl methionine via an N-methyl group. Formation of the berberine bridge is readily rationalized as an oxidative process in which the N-methyl group is oxidized to an iminium ion, and a cyclization to the aromatic ring occurs by virtue of the phenolic group.[19]

Reticuline is known as the immediate precursor of protoberberine alkaloids in plants.[20] Berberine is an alkaloid derived from tyrosine. L-DOPA and 4-hydroxypyruvic acid both come from L-tyrosine. Although two tyrosine molecules are used in the biosynthetic pathway, only the phenylethylamine fragment of the tetrahydroisoquinoline ring system is formed via DOPA, the remaining carbon atoms come from tyrosine via 4-hydroxyphenylacetaldehyde. L-DOPA loses carbon dioxide to form dopamine 1. Likewise, 4-hydroxypyruvic acid also loses carbon dioxide to form 4-hydroxyphenylacetaldehyde 2. Dopamine 1 then reacts with 4-hydroxy-phenylacetaldehyde 2 to form (S)-norcolaurine 3 in a reaction similar to the Mannich reaction. After oxidation and methylation by SAM, (S)-reticuline 4 is formed. (S)-reticuline serves as a pivotal intermediate to other alkaloids. Oxidation of the tertiary amine then occurs and an iminium ion is formed 5. In a Mannich-like reaction the ortho position to the phenol is nucleophilic, and electrons are pushed to form 6. Product 6 then undergoes keto-enol tautomerism to form (S)-scoulerine, which is then methylated by SAM to form (S)-tetrahydrocolumbamine 7. Product 7 is then oxidized to form the methylenedioxy ring from the ortho-methoxyphenol, via an O2-, NADPH- and cytochrome P-450-dependent enzyme, giving (S)-canadine 8. (S)-canadine is then oxidized to give the quaternary isoquinolinium system of berberine. This happens in two separate oxidation steps, both requiring molecular oxygen, with H2O2 and H2O produced in the successive processes.[21]

Berberine’s Anti-Cancer Effects

Berberine shows promise as a general anti-cancer agent, killing cancer cells and blocking proliferation in many cell studies [R, R]. Brain Cancer: Berberine induces cell death in human brain cancer (glioblastoma) cells. It had a potent anti-tumor effect on glioblastoma multiforme (GBM), which is the most common type of malignant brain cancer and known to be a grim diagnosis [R, RBreast Cancer: Coptis extracts (which contain berberine) enhance the anticancer effect of estrogen receptor antagonists on human breast cancer cells. The effect of Berberine on the growth of anoikis-resistant breast cancer cells was greater than treatment with doxorubicin, a drug commonly used to treat breast cancer [R, R]. Cervical Cancer: Berberine-induced cell death in human cervical cancer cells [R, R]. Colon Cancer: Berberine-induced cell death in colon tumor cells (through activation of an apoptosis-inducing factor). Derivatives of berberine are even stronger against colon cancer than the original compound [R, R]. Liver Cancer: Berberine-induced cell death in liver cancer cells. Berberine also inhibited Aspergillus flavus, a common fungal infection that produces cancer-causing compounds in the liver [R, R]. Lymphoma: Berberine is a potential anti-tumor agent for primary effusion lymphoma (PEL), which is a type of cancer associated with AIDS [R]. Oral Cancer: Berberine-induced cell death in human oral cancer cells [R, R]. Thyroid Cancer: Berberine reduced thyroid cancer cell growth [R, R]

Text under Construction

References

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  11. ^ Jump up to:
    a b Zhao H, Halicka HD, Li J, Darzynkiewicz Z. Berberine suppresses gero-conversion from cell cycle arrest to senescence. Aging (Albany) 2013; 6: 623–636. PMID 23974852, doi:10.18632/aging.100593
  12. ^ Darzynkiewicz Z, Zhao H, Halicka HD, Li J, Lee Y-S, Hsieh T-C, Wu J. In search of anti-aging modalities: evaluation of mTOR- and ROS/DNA damage- signaling by cytometry. Cytometry A 2014;85A:386-99. PMID 24677687, doi:10.1002/cyto.a.22452
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  18. ^ Zhang S, Zhang B, Xing K, Zhang X, Tian X, Dai W (2010). “Inhibitory effects of golden thread (Coptis chinensis) and berberine on Microcystis aeruginosa”. Water Science & Technology. 61 (3): 763–9. doi:10.2166/wst.2010.857. PMID 20150713.
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  21. ^ Dewick, P. (2009). Medicinal Natural Products: A Biosynthetic Approach (3rd ed.). West Sussex, England: Wiley. p. 358. ISBN 0-471-49641-3.

 

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