Bergamottin

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Bergamottin
Bergamottin.png
Identifiers
CAS number 7380-40-7 YesY
PubChem 5471349
ChemSpider 4581520 YesY
ChEMBL CHEMBL1078442 YesY
Jmol-3D images Image 1
Properties
Molecular formula C21H22O4
Molar mass 338.397 g/mol
Melting point 55 to 56 °C (131 to 133 °F; 328 to 329 K)
Except where noted otherwise, data are given for materials in their standard state (at 25 °C (77 °F), 100 kPa)
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Infobox references

Bergamottin is a natural furanocoumarin found principally in grapefruit juice. It is also found in the oil of bergamot orange, from which it was first isolated and from which its name is derived. To a lesser extent, bergamottin is also present in the essential oils of other citrus fruits. Along with the chemically related compound 6',7'-dihydroxybergamottin, it is believed to be responsible for the grapefruit juice effect, in which the consumption of the juice affects the metabolism of a variety of pharmaceutical drugs.[1]

Chemistry[edit]

In chemical terms, bergamottin and dihydroxybergamottin are linear furanocoumarins functionalized with side-chains derived from geraniol. They are inhibitors of some isoforms of the cytochrome P450 enzyme, in particular CYP3A4.[2] This prevents oxidative metabolism of certain drugs by the enzyme, resulting in an elevated concentration of drug in the bloodstream.

Under normal circumstances, the grapefruit juice effect is considered to be a negative interaction, and patients are often warned not to consume grapefruit or its juice when taking medication. However, some current research is focused on the potential benefits of cytochrome P450 inhibition.[3] Bergamottin, dihydroxybergamottin, or synthetic analogs may be developed as drugs that are targeted to increase the oral bioavailability of other drugs. Drugs that may have limited use because they are metabolized by CYP3A4 may become viable medications when taken with a CYP3A4 inhibitor because the dose required to achieve a necessary concentration in the blood would be lowered.[4]

Biosynthesis of bergamottin[edit]

Bergamottin is derived from components originating in the shikimate pathway.[5] The biosynthesis of this compound starts with the formation of the demethylsuberosin (3) product, which is formed via the alkylation of the umbelliferone (2) compound.[6] The alkylation of the umbelliferone is initiated with the use of dimethylallyl pyrophosphate, more commonly known as DMAPP. The cyclization of an alkyl group occurs to form marmesin (4), which is done in the presence of NADPH and oxygen along with a cytochrome P450 monooxygenase catalyst.[7] This process is then repeated twice more, first to remove the hydroxyisopropyl substituent from marmesin (4) to form psoralen (5), and then to add a hydroxyl group to form bergaptol (6).[8] Bergaptol (6) is next methylated with S-adenosyl methionine (SAM) to form bergapten (7). The final step in this biosynthesis is the attachment of a GPP, or geranyl pyrophosphate, to the newly methylated bergapten (7) to form the target molecule bergamottin (8).

Bergamottin biosynthesis.gif

References[edit]

  1. ^ David G. Bailey, J. Malcolm, O. Arnold, J. David Spence (1998). "Grapefruit juice-drug interactions". Br J Clin Pharmacol 46 (2): 101–110. doi:10.1046/j.1365-2125.1998.00764.x. PMC 1873672. PMID 9723817. 
  2. ^ Basavaraj Girennavar, Shibu M. Poulose, Guddadarangavvanahally K. Jayaprakasha, Narayan G. Bhat and Bhimanagouda S. Patila (2006). "Furocoumarins from grapefruit juice and their effect on human CYP 3A4 and CYP 1B1 isoenzymes". Bioorganic & Medicinal Chemistry 14 (8): 2606–2612. doi:10.1016/j.bmc.2005.11.039. PMID 16338240. 
  3. ^ E. C. Row, S. A. Brown, A. V. Stachulski and M. S. Lennard (2006). "Design, synthesis and evaluation of furanocoumarin monomers as inhibitors of CYP3A4". Org. Biomol. Chem. 4 (8): 1604–1610. doi:10.1039/b601096b. PMID 16604230. 
  4. ^ Christensen, Hege; Asberg, Anders; Holmboe, Aase-Britt; Berg, Knut Joachim (2002). "Coadministration of grapefruit juice increases systemic exposure of diltiazem in healthy volunteers". European Journal of Clinical Pharmacology 58 (8): 515–520. doi:10.1007/s00228-002-0516-8. PMID 12451428. 
  5. ^ Dewick, P. Medicinal Natural Products:A Biosynthetic Approach, 2nd ed., Wiley&Sons: West Sussex, England, 2001, p 145.
  6. ^ Bisagni, E. Synthesis of psoralens and analogues. J. Photochem. Photobiol. B. 1992, 14, 23-46.
  7. ^ Voznesensky, A. I.; Schenkman, J. B. The cytochrome P450 2B4-NADPH cytochrome P450 reductase electron transfer complex is not formed by charge-pairing. J. Biol. Chem. 1992, 267, 14669-14676.
  8. ^ Kent, U. M.; Lin, H. L.; Noon, K. R.; Harris, D. L.; Hollenberg, P. F. Metabolism of bergamottin by cytochromes P450 2B6 and 3A5. J. Pharmacol. Exp. Ther. 2006, 318, 992-1005.