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Citrus And Statins



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Citrus And Statins. —Citrus And Statins “” “How Foods and Drugs Collide” provided my first knowledge that 5-geranoxy psoralen (bergamottin) had been identified as the active agent in grapefruit juice implicated in interfering with the so-called statin drugs

( C&ENCitrus And Statins, Sept. 27, page 55 William L. Stanley Carmel, Calif. /articles/88/i49/Citrus-Statins.html 20101206 88 49 /magazine/88/8849.html /departments/letters.html Citrus And Statins Letters Citrus And Statins Chemical & Engineering News Citrus And Statins ACS 2009 IRS Form 990 Available The American Chemical Society’s 2009 Form 990 is now available on ACS’s website.

Chemical & Engineering News, 88(49), December 06, 2010 [Letters]  you will have to pay a fee or subscribe


free info from net

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 thegrapefruit juice effect in which the consumption of the juice affects the metabolism of a variety of pharmaceutical drugs.[1]


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

Normally, 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

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 SAM, S-Adenosyl methionine, 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


  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 1873672PMID 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.2005.11.039PMID 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/b601096bPMID 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/s00228-002-0516-8PMID 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



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DR ANTHONY MELVIN CRASTO, Worlddrugtracker, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his PhD from ICT ,1991, Mumbai, India, in Organic chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK- GENERICS LTD, Research centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Prior to joining Glenmark, he worked with major multinationals like Hoechst Marion Roussel, now sSanofi, Searle India ltd, now Rpg lifesciences, etc. he is now helping millions, has million hits on google on all organic chemistry websites. His New Drug Approvals, Green Chemistry International, Eurekamoments in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 25 year tenure, good knowledge of IPM, GMP, Regulatory aspects, he has several international drug patents published worldwide . He gas good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, polymorphism etc He suffered a paralytic stroke in dec 2007 and is bound to a wheelchair, this seems to have injected feul in him to help chemists around the world, he is more active than before and is pushing boundaries, he has one lakh connections on all networking sites, He makes himself available to all, contact him on +91 9323115463, amcrasto@gmail.com

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