Bergamottin (5-geranoxypsoralen) is a natural

furanocoumarin The furanocoumarins, or furocoumarins, are a class of organic chemical compounds produced by a variety of plants. Most of the plant species found to contain furanocoumarins belong to a handful of plant families. The families Apiaceae and Rutacea ...

found in the pulp of

pomelo The pomelo ( ), ''Citrus maxima'', is the largest citrus fruit from the family Rutaceae and the principal ancestor of the grapefruit. It is a natural, non-hybrid, citrus fruit, native to Southeast Asia. Similar in taste to a sweet grapefr ...

s and grapefruits. It is also found in the peel and pulp of the

bergamot orange ''Citrus bergamia'', the bergamot orange (pronounced ), is a fragrant citrus fruit the size of an orange, with a yellow or green color similar to a lime, depending on ripeness. Genetic research into the ancestral origins of extant citrus cult ...

, from which it was first isolated and from which its name is derived.

Chemistry

Bergamottin and dihydroxybergamottin are linear furanocoumarins functionalized with side chains derived from

geraniol Geraniol is a monoterpenoid and an alcohol. It is the primary component of citronella oil and is a primary component of rose oil, palmarosa oil. It is a colorless oil, although commercial samples can appear yellow. It has low solubility in w ...

. They are inhibitors of some

isoforms A protein isoform, or "protein variant", is a member of a set of highly similar proteins that originate from a single gene or gene family and are the result of genetic differences. While many perform the same or similar biological roles, some iso ...

of the

cytochrome P450 Cytochromes P450 (CYPs) are a superfamily of enzymes containing heme as a cofactor that functions as monooxygenases. In mammals, these proteins oxidize steroids, fatty acids, and xenobiotics, and are important for the clearance of various co ...

enzyme, in particular CYP3A4. 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. Bergamottin, dihydroxybergamottin, or synthetic analogs may be developed as drugs that are targeted to increase the oral

bioavailability In pharmacology, bioavailability is a subcategory of absorption and is the fraction (%) of an administered drug that reaches the systemic circulation. By definition, when a medication is administered intravenously, its bioavailability is 100%. Ho ...

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. An example of the use of this effect in current medicines is the co-administration of

ritonavir Ritonavir, sold under the brand name Norvir, is an antiretroviral drug used along with other medications to treat HIV/AIDS. This combination treatment is known as highly active antiretroviral therapy (HAART). Ritonavir is a protease inhibitor ...

, a potent inhibitor of the CYP3A4 and

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 ...

isoforms of

, with other antiretroviral drugs. Although

inhibits HIV replication in its own right, its use in these treatment regimens is to enhance the bioavailability of other agents through inhibition of the enzymes that metabolize them.

Biosynthesis

Bergamottin is derived from components originating in the

shikimate pathway The shikimate pathway (shikimic acid pathway) is a seven-step metabolic pathway used by bacteria, archaea, fungi, algae, some protozoans, and plants for the biosynthesis of folates and aromatic amino acids (tryptophan, phenylalanine, and tyrosine) ...

. 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. The alkylation of the umbelliferone is initiated with the use of

dimethylallyl pyrophosphate Dimethylallyl pyrophosphate (DMAPP; or alternatively, dimethylallyl diphosphate (DMADP); also isoprenyl pyrophosphate) is an isoprenoid precursor. It is a product of both the mevalonate pathway and the MEP pathway of isoprenoid precursor biosynt ...

, more commonly known as DMAPP. The cyclization of an alkyl group occurs to form

marmesin Marmesin (nodakenetin) is a chemical compound precursor in psoralen and linear furanocoumarins biosynthesis Biosynthesis is a multi-step, enzyme-catalyzed process where substrates are converted into more complex products in living organisms. I ...

(4), which is done in the presence of NADPH and oxygen along with a cytochrome P450 monooxygenase catalyst. 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).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. Bergaptol (6) is next methylated with

S-adenosyl methionine ''S''-Adenosyl methionine (SAM), also known under the commercial names of SAMe, SAM-e, or AdoMet, is a common cosubstrate involved in methyl group transfers, transsulfuration, and aminopropylation. Although these anabolic reactions occur throug ...

(SAM) to form bergapten (7). The final step in this biosynthesis is the attachment of a GPP, or

geranyl pyrophosphate Geranyl pyrophosphate (GPP), also known as geranyl diphosphate (GDP), is the pyrophosphate ester of the terpenoid geraniol. Its salts are colorless. It is a precursor to many natural products. Occurrence GPP is an intermediate in the isopreno ...

, to the newly methylated bergapten (7) to form the target molecule bergamottin (8).

References

{{Coumarin CYP3A4 inhibitors Furanocoumarins Terpeno-phenolic compounds