Berberine is a

quaternary ammonium In chemistry, quaternary ammonium cations, also known as quats, are positively charged polyatomic ions of the structure , R being an alkyl group or an aryl group. Unlike the ammonium ion () and the primary, secondary, or tertiary ammonium cations ...

salt from the protoberberine group of benzylisoquinoline

alkaloid Alkaloids are a class of basic, naturally occurring organic compounds that contain at least one nitrogen atom. This group also includes some related compounds with neutral and even weakly acidic properties. Some synthetic compounds of similar ...

s found in such plants as ''

Berberis vulgaris ''Berberis vulgaris'', also known as common barberry, European barberry or simply barberry, is a shrub in the genus ''Berberis'' native to the Old World. It produces edible but sharply acidic berries, which people in many countries eat as a ta ...

'' (barberry), ''

Berberis aristata ''Berberis aristata'', also known as Indian barberry, "chutro" or "sumbal" or tree turmeric , is a shrub belonging to the family Berberidaceae and the genus ''Berberis''. The genus comprises approximately 450-500 species of deciduous evergreen ...

'' (tree turmeric), ''

Mahonia aquifolium ''Mahonia aquifolium'', the Oregon grape or holly-leaved barberry, is a species of flowering plant in the family Berberidaceae, native to western North America. It is an evergreen shrub growing tall and wide, with pinnate leaves consisting of sp ...

'' (Oregon grape), ''

Hydrastis canadensis ''For the magazine from West Virginia see Goldenseal (magazine)'' Goldenseal (''Hydrastis canadensis''), also called orangeroot or yellow puccoon, is a perennial herb in the buttercup family Ranunculaceae, native to North America. It may be di ...

'' (goldenseal), ''

Xanthorhiza simplicissima ''Xanthorhiza simplicissima'' (yellowroot) is the only member of the genus ''Xanthorhiza'', and one of very few genera in the family Ranunculaceae with a woody stem (the other notable example being ''Clematis''). It is native to the eastern Uni ...

'' (yellowroot), ''

Phellodendron amurense ''Phellodendron amurense'' is a species of tree in the family Rutaceae, commonly called the Amur cork tree. It is a major source of '' huáng bò'' ( or 黄檗), one of the 50 fundamental herbs used in traditional Chinese medicine. The Ainu pe ...

'' (Amur cork tree), ''

Coptis chinensis ''Coptis chinensis'', the Chinese goldthread, is a species of goldthread flowering plant native to China. Etymology *''Coptis chinensis'' Franch. var. ''chinensis''

'' (Chinese goldthread), ''

Tinospora cordifolia ''Tinospora cordifolia'' (common names gurjo, heart-leaved moonseed, guduchi or giloy) is a herbaceous vine of the family Menispermaceae indigenous to tropical regions of the Indian subcontinent. It has been used in Ayurveda to treat various diso ...

'', ''

Argemone mexicana ''Argemone mexicana'' (Mexican poppy, Mexican prickly poppy, flowering thistle, cardo or cardosanto) is a species of poppy found in Mexico and now widely naturalized in many parts of the world. An extremely hardy pioneer plant, it is tolerant o ...

'' (prickly poppy), and ''

Eschscholzia californica ''Eschscholzia californica'', the California poppy, golden poppy, California sunlight or cup of gold, is a species of flowering plant in the family Papaveraceae, native to the United States and Mexico. It is cultivated as an ornamental plant f ...

'' (Californian poppy). Berberine is usually found in the roots,

rhizome In botany and dendrology, a rhizome (; , ) is a modified subterranean plant stem that sends out roots and shoots from its nodes. Rhizomes are also called creeping rootstalks or just rootstalks. Rhizomes develop from axillary buds and grow hori ...

s, stems, and bark. Due to its yellow color, ''Berberis'' species were used to dye wool, leather, and wood. Under

ultraviolet light Ultraviolet (UV) is a form of electromagnetic radiation with wavelength from 10 nm (with a corresponding frequency around 30 PHz) to 400 nm (750 THz), shorter than that of visible light, but longer than X-rays. UV radiation i ...

, berberine shows a strong yellow

fluorescence Fluorescence is the emission of light by a substance that has absorbed light or other electromagnetic radiation. It is a form of luminescence. In most cases, the emitted light has a longer wavelength, and therefore a lower photon energy, tha ...

, making it useful in

histology Histology, also known as microscopic anatomy or microanatomy, is the branch of biology which studies the microscopic anatomy of biological tissues. Histology is the microscopic counterpart to gross anatomy, which looks at larger structures vis ...

for

staining Staining is a technique used to enhance contrast in samples, generally at the microscopic level. Stains and dyes are frequently used in histology (microscopic study of biological tissues), in cytology (microscopic study of cells), and in the ...

heparin Heparin, also known as unfractionated heparin (UFH), is a medication and naturally occurring glycosaminoglycan. Since heparins depend on the activity of antithrombin, they are considered anticoagulants. Specifically it is also used in the treatm ...

mast cell A mast cell (also known as a mastocyte or a labrocyte) is a resident cell of connective tissue that contains many granules rich in histamine and heparin. Specifically, it is a type of granulocyte derived from the myeloid stem cell that is a par ...

s. As a natural dye, berberine has a

color index In astronomy, the color index is a simple numerical expression that determines the color of an object, which in the case of a star gives its temperature. The lower the color index, the more blue (or hotter) the object is. Conversely, the large ...

of 75160.

Research and adverse effects

The safety of using berberine for any condition is not adequately defined by high-quality clinical research. Its potential for causing

adverse effect An adverse effect is an undesired harmful effect resulting from a medication or other intervention, such as surgery. An adverse effect may be termed a "side effect", when judged to be secondary to a main or therapeutic effect. The term complica ...

s is high, including untoward interactions with

prescription drug A prescription drug (also prescription medication or prescription medicine) is a pharmaceutical drug that legally requires a medical prescription to be dispensed. In contrast, over-the-counter drugs can be obtained without a prescription. The rea ...

s, reducing the intended effect of established therapies. Berberine weakly inhibits the

CYP2D6 Cytochrome P450 2D6 (CYP2D6) is an enzyme that in humans is encoded by the ''CYP2D6'' gene. ''CYP2D6'' is primarily expressed in the liver. It is also highly expressed in areas of the central nervous system, including the substantia nigra. CYP2D ...

and

CYP3A4 Cytochrome P450 3A4 (abbreviated CYP3A4) () is an important enzyme in the body, mainly found in the liver and in the intestine. It oxidizes small foreign organic molecules (xenobiotics), such as toxins or drugs, so that they can be removed from t ...

enzymes which are involved in metabolism of

endogenous Endogenous substances and processes are those that originate from within a living system such as an organism, tissue, or cell. In contrast, exogenous substances and processes are those that originate from outside of an organism. For example, es ...

substances and

xenobiotic A xenobiotic is a chemical substance found within an organism that is not naturally produced or expected to be present within the organism. It can also cover substances that are present in much higher concentrations than are usual. Natural compo ...

s, including many prescription drugs. It is particularly unsafe for use in newborns and infants.

Biosynthesis

The

berberine has a tetracyclic skeleton derived from a benzyltetrahydroisoquinoline system with the incorporation of an extra carbon atom as a bridge. Formation of the berberine bridge is rationalized as an oxidative process in which the ''N''-

methyl group In organic chemistry, a methyl group is an alkyl derived from methane, containing one carbon atom bonded to three hydrogen atoms, having chemical formula . In formulas, the group is often abbreviated as Me. This hydrocarbon group occurs in many ...

, supplied by ''S''-adenosyl methionine (SAM), is oxidized to an

iminium ion In organic chemistry, an iminium cation is a polyatomic ion with the general structure . They are common in synthetic chemistry and biology. Structure Iminium cations adopt alkene-like geometries. The central C=N unit is nearly coplanar with al ...

, and a cyclization to the aromatic ring occurs by virtue of the phenolic group.

Reticuline Reticuline is a chemical compound found in a variety of plants including ''Lindera aggregata'', ''Annona squamosa'', and ''Ocotea fasciculata'' (also known as ''Ocotea duckei''). It is based on the benzylisoquinoline structure. Reticuline is one ...

is the immediate precursor of protoberberine alkaloids in plants. Berberine is an alkaloid derived from

tyrosine -Tyrosine or tyrosine (symbol Tyr or Y) or 4-hydroxyphenylalanine is one of the 20 standard amino acids that are used by cells to synthesize proteins. It is a non-essential amino acid with a polar side group. The word "tyrosine" is from the Gr ...

. L-DOPA and 4-hydroxypyruvic acid both come from L-tyrosine. Although two

molecules are used in the biosynthetic pathway, only the

phenethylamine Phenethylamine (PEA) is an organic compound, natural monoamine alkaloid, and trace amine, which acts as a central nervous system stimulant in humans. In the brain, phenethylamine regulates monoamine neurotransmission by binding to trace amin ...

fragment of the

tetrahydroisoquinoline Tetrahydroisoquinoline (TIQ or THIQ) is an organic compound with the chemical formula C9H11N. Classified as a secondary amine, it is derived from isoquinoline by hydrogenation. It is a colorless viscous liquid that is miscible with most organic s ...

ring system is formed via DOPA, the remaining carbon atoms come from

via 4-hydroxyphenylacetaldehyde. L-DOPA loses carbon dioxide to form

dopamine Dopamine (DA, a contraction of 3,4-dihydroxyphenethylamine) is a neuromodulatory molecule that plays several important roles in cells. It is an organic compound, organic chemical of the catecholamine and phenethylamine families. Dopamine const ...

1. Likewise, 4-hydroxypyruvic acid also loses carbon dioxide to form 4-hydroxyphenylacetaldehyde 2.

Dopamine Dopamine (DA, a contraction of 3,4-dihydroxyphenethylamine) is a neuromodulatory molecule that plays several important roles in cells. It is an organic compound, organic chemical of the catecholamine and phenethylamine families. Dopamine const ...

1 then reacts with 4-hydroxy-phenylacetaldehyde 2 to form (''S'')-norcolaurine 3 in a reaction similar to the

Mannich reaction In organic chemistry, the Mannich reaction is a three-component organic reaction that involves the amino alkylation of an acidic proton next to a carbonyl () functional group by formaldehyde () and a primary or secondary amine () or ammonia (). ...

. 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 In chemistry, amines (, ) are compounds and functional groups that contain a basic nitrogen atom with a lone pair. Amines are formally derivatives of ammonia (), wherein one or more hydrogen atoms have been replaced by a substituent such a ...

then occurs and an

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 In organic chemistry, alkenols (shortened to enols) are a type of reactive structure or intermediate in organic chemistry that is represented as an alkene ( olefin) with a hydroxyl group attached to one end of the alkene double bond (). The t ...

to form (''S'')-scoulerine, which is then methylated by SAM to form (''S'')-tetrahydrocolumbamine 7. Product 7 is then oxidized to form the

methylenedioxy Methylenedioxy is the term used in the field of chemistry, particularly in organic chemistry, for a functional group with the structural formula R-O-CH2-O-R' which is connected to the rest of a molecule by two chemical bonds. The methylenedioxy gr ...

ring from the ''ortho''-methoxyphenol, via an O₂-, NADPH- and

cytochrome P450 Cytochromes P450 (CYPs) are a Protein superfamily, superfamily of enzymes containing heme as a cofactor (biochemistry), cofactor that functions as monooxygenases. In mammals, these proteins oxidize steroids, fatty acids, and xenobiotics, and are ...

-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.

References

{{Sigma receptor modulators Aromatase inhibitors Benzodioxoles CYP2D6 inhibitors CYP3A4 inhibitors DNA-binding substances Isoquinoline alkaloids Nitrogen heterocycles Quaternary ammonium compounds