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 ( ; or pummelo, ''Citrus maxima''), also known as a shaddock, is the largest citrus fruit. It is an ancestor of several cultivated citrus species, including the bitter orange and the grapefruit. It is a natural, non-hybrid citrus fr ...

s and

grapefruit The grapefruit (''Citrus'' × ''paradisi'') is a subtropical citrus tree known for its relatively large, sour to semi-sweet, somewhat bitter fruit. The flesh of the fruit is segmented and varies in color from pale yellow to dark red. Grapefru ...

s. 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 colour similar to a lime, depending on ripeness. Genetic research into the ancestral origins of extant citrus cul ...

, 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 and palmarosa oil. It is a colorless oil, although commercial samples can appear yellow. It has low solubility i ...

. 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 and are the result of genetic differences. While many perform the same or similar biological roles, some isoforms have uniqu ...

of the

cytochrome P450 Cytochromes P450 (P450s or CYPs) are a Protein superfamily, superfamily of enzymes containing heme as a cofactor (biochemistry), cofactor that mostly, but not exclusively, function as monooxygenases. However, they are not omnipresent; for examp ...

enzyme, in particular

CYP3A4 Cytochrome P450 3A4 (abbreviated CYP3A4) () is an important enzyme in the body, mainly found in the liver and in the intestine, which in humans is encoded by ''CYP3A4'' gene. It organic redox reaction, oxidizes small foreign organic molecules ( ...

. 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%. H ...

of other drugs. Drugs that may have limited use because they are metabolized by

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 medication used along with other medications to treat HIV/AIDS. This combination treatment is known as highly active antiretroviral therapy (HAART). Ritonavir is a protease inhi ...

, a potent inhibitor of the

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. CYP2 ...

isoforms of

, with other

antiretroviral The management of HIV/AIDS normally includes the use of multiple antiretroviral drugs as a strategy to control HIV infection. There are several classes of antiretroviral agents that act on different stages of the HIV life-cycle. The use of mu ...

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 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, 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. 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 thro ...

(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).

References

{{Coumarin CYP3A4 inhibitors Furanocoumarins Terpeno-phenolic compounds