Bergamottin

A natural furanocoumarin

Bergamottin is a natural furanocoumarin found in grapefruits, pomelos, and bergamot oranges. It's also found in grapefruit juice and bergamot oil.

Bergamottin is a cytochrome P450 inhibitor. It can increase plasma levels of drugs that are normally catabolized by CYP3A4.

Bergamottin has been shown to have anti-oxidative, anti-inflammatory, and anti-cancer properties.

Bergamottin's empirical formula is C21H22O4, and its molar mass is 338.40 g/mol.

Bergamottin is also known as:

• 5-geranoxypsoralen
• 7H-Furo[3,2-g]benzopyran-7-one, 4[(2E)-3,7-dimethyl-2,6-octadien-1-yl]oxy

Human Biological Effects

Bergamottin is a natural furanocoumarin found abundantly in citrus fruits—most notably in grapefruit peel, bergamot orange (Citrus bergamia), and various other Rutaceae species. It is famously recognized as a primary chemical driver behind the classic "grapefruit juice effect" on human drug pharmacokinetics, alongside several notable cellular and metabolic activities:

1. Inhibition of Cytochrome P450 Enzymes (The "Grapefruit Effect")

• CYP3A4 Inactivation: Bergamottin acts as a potent mechanism-based (suicide) inactivator of hepatic and intestinal cytochrome P450 3A4 (CYP3A4), as well as CYP2C9 and CYP1A2.
• Pharmacokinetic Alteration: By irreversibly binding to and destroying CYP3A4 enzymes located in the intestinal enterocytes, bergamottin dramatically reduces the first-pass metabolism of various orally administered medications (such as certain statins, calcium channel blockers, and immunosuppressants). This leads to a massive, unintended spike in their systemic bioavailability and plasma concentrations, risking clinical overdose or toxicity.

2. P-Glycoprotein (P-gp) and Efflux Modulation

• Efflux Pump Inhibition: Beyond phase I metabolic enzymes, bergamottin interacts with cellular membrane transporters like P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP).
• Reversal of Multidrug Resistance (MDR): By competitively inhibiting P-gp-mediated drug efflux, bergamottin can increase intracellular accumulation of foreign compounds and chemotherapeutic agents in resistant cell lines, enhancing their cellular retention and efficacy.

3. Anti-Cancer and Pro-Apoptotic Pathways

• Signaling Interruption: In various preclinical human cancer models (including multiple myeloma, prostate cancer, and leukemia), bergamottin suppresses tumor cell proliferation. It downregulates critical survival and growth pathways, including the STAT3, PI3K/Akt/mTOR, and NF-κB cascades.
• Cell Cycle Arrest: It prompts targeted cell cycle arrest at the G0/G1 or S phases and triggers caspase-driven apoptosis while downregulating anti-apoptotic proteins like Bcl-2, Bcl-xL, and survivin.

4. Dermal and Phototoxic Considerations

• Photosensitization: Like many linear furanocoumarins (such as psoralens), bergamottin can intercalate into DNA when exposed to ultraviolet (UVA) light, producing phototoxic skin reactions or contact dermatitis if applied topically in high concentrations from unrefined citrus essential oils (such as expressed bergamot oil).

Solubility Profile

• Lipophilic Nature: Because of its long hydrophobic geranyl substituent attached to the furanocoumarin core, bergamottin is fat-soluble (lipophilic) and practically insoluble in water. It partitions readily into alcohol, fixed plant oils, and organic solvents.

Studies

Cancer

• A novel role of bergamottin in attenuating cancer associated cachexia.
• These results suggest that the suppression of MMP expression contributes, at least in part, to the antitumor activity of bergamottin.
• Bergamottin isolated from Citrus bergamia exerts in vitro and in vivo antitumor activity in lung adenocarcinoma.
• Bergamottin induces chemosensitization and apoptosis through the inhibition of STAT3 signaling pathway in tumor cells.
• Bergamottin, a natural furanocoumarin abundantly present in grapefruit juice, suppresses the invasiveness of human glioma cells.
• Bergamottin suppresses metastasis of lung cancer cells.
• Bergamottin exerts anticancer effects on human colon cancer cells.
• Bergamottin induces DNA damage and inhibits malignant progression in melanoma.

COVID-19

• Bergamottin and PAP-1 induced ACE2 degradation to alleviate infection of SARS-CoV-2.
• Bergamottin inhibits SARS-CoV-2 infection.

Drug Inhibitor

Bergamottin and its Role as a Drug Inhibitor

Bergamottin is a member of the furanocoumarin family and is most commonly found in grapefruit juice. Bergamottin is a known drug inhibitor of cytochrome P450 34A.

For this reason, it is often recommended that patients avoid consumption of grapefruit juice if currently prescribed medication such as statins, antihistamines, and drugs in several other classes. This drug interaction is often referred to as “the grapefruit effect” and can cause the compound to remain in the body for a prolonged period of time; which may ultimately lead to health risks in some patients.

LPS Lung Injury / LPS Endotoxic Shock

• Bergamottin protects against LPS-induced endotoxic shock by regulating the NF-κB signaling pathway.
• Bergamottin alleviates LPS-induced acute lung injury.

Obesity

Bergamottin inhibits adipogenesis in 3T3-L1 cells and weight regulation in diet-induced obese mice.