Ingredients6,7-Dihydroxybergamottin — formally designated 6′,7′-dihydroxybergamottin (the primes indicating positions on the geranyloxy side chain) — is the predominant name used in the scientific and pharmacological literature. Its common abbreviation is DHB. The substance was isolated from grapefruit juice using TLC and identified, using NMR and MS, as 6′,7′-dihydroxybergamottin, with the molecular formula C₂₁H₂₄O₆ and a molecular weight of 372 Da, classified as a furanocoumarin (psoralen) compound. Some sources alternatively list the molecular formula as C₂₁H₂₂O₇ with a molecular weight of 386.40 g/mol, reflecting different hydration or protonation states encountered in the literature; the CAS number is 37686-84-3.
DHB is a naturally occurring inhibitor of cytochrome P450 3A4 and a furanocoumarin — a class of organic compounds primarily found in plants, specifically in species of the Apiaceae and Rutaceae families. Within that structural class, it belongs to the bergamottin derivative subgroup: bergamottin derivatives are known for their potent effects on cytochrome P450 enzyme systems and drug metabolism pathways.
6′,7′-Dihydroxybergamottin is a natural furanocoumarin found in pomelos, grapefruits, and sour oranges, in both the peel and the pulp. 6′,7′-Dihydroxybergamottin and bergamottin are dominant furanocoumarins in all tested grapefruits, while some pomelos have dominant epoxybergamottin, and some have dominant 6′,7′-dihydroxybergamottin and bergamottin. The contents of furanocoumarins are low or below detection in sweet oranges, mandarins, lemons, and trifoliate oranges.
Pomelos and their hybrids, such as grapefruits and sour oranges (Citrus aurantium L.), present high amounts of furanocoumarins in the pulp, whereas mandarins and sweet oranges present the lowest furanocoumarin content. An analysis of Chinese pomelo varieties found that the total content of the four major furanocoumarins in pomelo juices from high to low was: Guanximi pomelo > Liangping pomelo > Pinghemi pomelo > grapefruit > Huyou > Shatian pomelo.
DHB has also been identified in Kaffir lime (Citrus hystrix DC.) fruit peel: two known furanocoumarins, namely 6′,7′-dihydroxybergamottin and oxypeucedanin hydrate, were isolated from Kaffir lime fruit peel using a nitric oxide scavenging effect-guided fractionation assay. One commercial source claims extraction from the roots of certain Urtica (nettle) species, though this has not been independently confirmed in peer-reviewed literature to the same extent as the citrus sources.
The production of 6′,7′-dihydroxybergamottin involves either direct plant extraction or chemical synthesis, with raw materials differing depending on the method used. In the natural extraction route, the primary raw material is grapefruit peel or juice, particularly from varieties with high furanocoumarin content. The compound is found in relatively low concentrations, so large volumes of grapefruit material are required. The extraction process typically begins with grapefruit oil or juice, followed by solvent extraction using organic solvents such as methanol or ethyl acetate. The resulting crude extract is then purified through liquid-liquid partitioning, column chromatography, or HPLC to isolate 6′,7′-dihydroxybergamottin in sufficient purity.
Authentic 6′,7′-dihydroxybergamottin was synthesized and found to be identical to the compound isolated from grapefruit juice by comparing the proton NMR spectrum, HPLC retention time, EI-MS and CI-MS data. Synthesized forms are widely used in pharmacological research. In dietary supplement contexts, DHB is sold primarily as a standardized powder or encapsulated extract, often sourced from grapefruit. It is marketed in combination products aimed at enhancing the bioavailability of co-administered compounds (see Section 5).
DHB as an isolated or standardized chemical entity has no documented traditional use. It is a modern pharmacological isolate, first formally identified from grapefruit juice in a 1996 publication. However, the fruit sources from which it is derived have long histories of use in traditional medicine systems across multiple cultures.
Grapefruit (Citrus paradisi) was developed as a hybrid of the pomelo and sweet orange, likely in Barbados in the early 18th century, and entered widespread cultivation in the 19th century. It does not carry the depth of traditional medicinal documentation that older citrus species possess. By contrast, the pomelo (Citrus maxima or Citrus grandis) has been cultivated in Southeast Asia for several thousand years and is mentioned in classical Chinese and Ayurvedic literature for its digestive and tonic properties. Sour orange (Citrus aurantium), another DHB-containing species, has an extensive history in Traditional Chinese Medicine, Ayurveda, and Mediterranean folk medicine, where the peel (zhi shi or zhi ke) was used as a digestive aid, expectorant, and circulatory stimulant.
Kaffir lime (Citrus hystrix DC.), another source of DHB, is used in Southeast Asian traditional medicine. Its peel and leaves are used in Thai, Indonesian, and Malay traditional healing for digestive complaints, as a fragrance component, and in ritual cleansing practices.
In all these traditions, the fruit or peel preparations were used as whole materials containing complex mixtures. The contribution of DHB specifically to any therapeutic or physiological effect of these preparations was not recognized or described historically; that recognition emerged only from modern analytical chemistry and pharmacology.
Bergamottin (i.e., 5-geranoxypsoralen) is a natural furanocoumarin originally detected in bergamot oil (Citrus bergamia) and is mainly responsible, together with 6′,7′-dihydroxybergamottin (DHB), for "grapefruit juice/drug" interactions. DHB can be considered the dihydroxylated metabolite of bergamottin: bergamottin has systemic availability and is metabolized in vivo to 6′,7′-dihydroxybergamottin. Both compounds share a linear furanocoumarin (psoralen) backbone but differ in the geranyloxy side chain substituents.
The primary and best-documented mechanism of DHB is mechanism-based (suicide) inactivation of cytochrome P450 3A4 (CYP3A4). DHB, a natural furanocoumarin found in grapefruit, is known to cause mechanism-based inactivation (MBI) of several cytochrome P450 enzymes in humans, including CYP3A4. Human CYP3A4 oxidizes over 50% of administered drugs, along with natural compounds, some of which can act as inhibitors. The mechanism-based (suicide) inhibition of CYP3A4 is the most common mechanism that could lead to clinically significant drug-drug interactions, toxicity, and therapeutic failures.
In purified enzyme preparations, human liver microsomes, and human CYP3A4 expressed in E. coli membrane, 6′,7′-dihydroxybergamottin proved to be a potent NADPH- and time-dependent inactivator of CYP3A4. The inhibition of 6β-hydroxytestosterone formation activity in human liver microsomes was time- and concentration-dependent as well as requiring catalytic turnover of 6′,7′-dihydroxybergamottin, which suggested that the inhibition resulted from mechanism-based inactivation of P450 3A4.
A 2025 quantum mechanics/molecular mechanics (QM/MM) computational study elucidated the molecular mechanism at high resolution: molecular docking and molecular dynamics simulations were used to identify a plausible catalytic binding pose of DHB within CYP3A4. QM/MM calculations explored two possible reaction pathways. Path A involves attack by compound I (Cpd I) at the C5 position of the furan moiety, leading to γ-ketoenal formation, while Path B targets the C4 position, yielding an epoxide. Path A exhibits a much lower activation energy barrier, indicating a strong kinetic preference. Additionally, the γ-ketoenal is thermodynamically more stable than the epoxide. Thus, even if the epoxide forms initially, it is likely to rearrange into the γ-ketoenal, either within the enzyme or in aqueous solution.
Studies with recombinant CYP3A4 revealed that 6′,7′-dihydroxybergamottin is a mechanism-based inactivator, which supports the idea that loss of CYP3A4 results from accelerated degradation of the enzyme. In cellular models, DHB and ketoconazole, a well-known inhibitor of CYP3A4, inhibited nifedipine oxidation in a concentration-dependent manner, and inhibition of CYP3A4 activity by DHB includes the inhibition of NADPH-cytochrome P450 reductase (POR) activity.
The inhibition operates on two timescales: 6′,7′-dihydroxybergamottin acts initially by competitive inhibition followed by mechanism-based inactivation of recombinant CYP3A4, consistent with the in vivo effects observed in humans. All six major furanocoumarins in grapefruit juice showed stronger CYP3A inhibitory potencies after preincubation in the presence of NADPH, suggesting that both competitive and mechanism-based inhibition occur in grapefruit juice–drug interactions.
DHB's inhibitory activity is not limited exclusively to CYP3A4. Paradisin and 6′,7′-dihydroxybergamottin inhibit the in vitro activity of CYP1A2, CYP1B1, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Among the major grapefruit furanocoumarins, different compounds inhibit CYP3A4 to different degrees in vitro, in the order: paradisins > 6′,7′-dihydroxybergamottin > bergamottin > bergaptol.
DHB also affects membrane drug-transport proteins, which can independently modify drug absorption. In P-glycoprotein (P-gp) studies, the furanocoumarin 6′,7′-epoxybergamottin was the most potent inhibitor of P-gp-mediated talinolol transport (IC₅₀ = 0.7 μmol/L), followed by 6′,7′-dihydroxybergamottin (IC₅₀ = 34 μmol/L); bergamottin produced no inhibition at concentrations up to 10 μmol/L.
For organic anion-transporting polypeptides (OATPs), the picture is different: 6′,7′-dihydroxybergamottin had modest inhibitory activity against P-gp (IC₅₀ = 33 μmol/L). In contrast, grapefruit, orange, and apple juices at 5% of normal strength markedly reduced human OATP activity. 6′,7′-Dihydroxybergamottin potently inhibited rat oatp3 and oatp1 (IC₅₀ = 0.28 μmol/L). Fruit juices and their constituents are more potent inhibitors of OATPs than of P-glycoprotein activities, and can thereby reduce oral drug bioavailability.
Separate from its enzyme-inhibitory properties, preclinical cell-based studies have investigated DHB's anti-inflammatory activity. DHB is an effective inhibitor of lipopolysaccharide (LPS)-induced nitric oxide (NO) and prostaglandin E₂ production in RAW 264.7 macrophage cells. The inhibitory effects of DHB include dose-dependent decreases in the expression of inducible NO synthase and cyclooxygenase-2 proteins. Additionally, DHB inhibited LPS-interferon-γ-induced NO and iNOS production in RAW264.7 cells and COX-2 production in HT-29 and HCT116 colon cancer cells, with IC₅₀ values of 16.16 ± 1.08, 18.63 ± 1.42, 18.19 ± 0.95, and 17.53 ± 0.88 μg/mL, respectively. These are in vitro findings only; no clinical translation has been established.
Grapefruit is a moderate to strong inactivator of CYP3A4, which metabolizes up to 50% of marketed drugs. Furanocoumarins, including bergamottin (BGT) and 6,7-dihydroxybergamottin (DHB), are among the most important CYP3A4 inactivators present in grapefruit. The "grapefruit effect" is characterized by a time-dependent CYP3A4 inhibition lasting more than 24 hours, and by the more pronounced effect on intestinal rather than hepatic CYP3A4. Drugs with low oral bioavailability related to CYP3A4 metabolism bear a high risk of interaction, and one glass of juice (200–250 mL, equivalent to 1 fruit) might already cause a clinically relevant effect.
Inhibition is localized primarily in the gut, as demonstrated by a lack of effect on the elimination half-life of orally administered substrates and on the pharmacokinetics of intravenously administered substrates. The increase in systemic drug exposure can be sufficient to produce adverse events, such as muscle pain with some statins and severe hypotension with some calcium channel blockers.
DHB was formally identified as the principal CYP3A inhibitor in grapefruit juice in a landmark 1996 investigation. Grapefruit juice was extracted into methylene chloride and chromatographed by HPLC, and the effect of the HPLC eluent on CYP3A activity was assessed by measuring 6β-hydroxytestosterone formation in rat liver microsomes. Significant inhibition was associated with a fraction of HPLC eluent containing a single peak with a retention time of 16 minutes. The substance was isolated using TLC and identified by NMR and MS as 6′,7′-dihydroxybergamottin. The concentration required to inhibit 6β-hydroxytestosterone formation by 50% was 25 μM.
Grapefruit juice reduced CYP3A activity to a significantly greater extent (p < 0.05) than did orange juice, which contained no measurable 6′,7′-dihydroxybergamottin (28.6% vs. 62.2% of control activity). The addition of 6′,7′-dihydroxybergamottin (30 μM) to orange juice decreased CYP3A activity to values comparable to those observed with grapefruit juice. 6′,7′-Dihydroxybergamottin is a potent inhibitor of CYP3A activity, accounts for the difference in inhibition between grapefruit juice and orange juice in vitro, and may be primarily responsible for the effects of grapefruit juice on cytochrome P450 activity in humans.
Several human clinical trials have investigated the role of DHB in grapefruit juice–felodipine interactions. A 1998 randomized crossover study in 12 healthy men (Bailey et al.) tested fractionated grapefruit juice: the effect of supernatant and particulate fractions, grapefruit juice, and water on the pharmacokinetics of oral felodipine were assessed in 12 healthy men in a randomized, 4-way crossover study. The amounts of naringin and 6′,7′-dihydroxybergamottin in the supernatant fraction were 148 mg and 1.85 mg, compared with 7 mg and 0.60 mg in the particulate fraction. The AUC and peak concentration of felodipine were higher with both fractions and grapefruit juice compared with water. The study concluded, however, that naringin and 6′,7′-dihydroxybergamottin are not the major active ingredients, although they may contribute to the grapefruit juice–felodipine interaction.
A separate and methodologically distinct 2004 clinical study by Kakar et al. specifically designed to isolate DHB's contribution reached a different conclusion. The objective was to assess the contribution of DHB to the inhibitory effect of grapefruit juice toward intestinal CYP3A4. An aqueous extract was prepared from grapefruit juice and various furanocoumarin concentrations measured by HPLC. Five healthy volunteers were given a single tablet of felodipine (10 mg) with whole grapefruit juice, orange juice-containing serum, or plain orange juice. The concentration of DHB in the serum was comparable to that measured in whole grapefruit juice (38 μmol/L versus 43 μmol/L), and the concentrations of other known furanocoumarins were well below the lowest published concentration required to inhibit catalytic activity by 50%. The interaction between grapefruit juice serum and felodipine could be attributed largely to DHB, establishing DHB as an important contributor to the grapefruit juice effect.
A third clinical study investigated unprocessed grapefruit rather than juice. In a randomized four-way crossover study, the oral pharmacokinetics of felodipine were determined after administration of a felodipine 10 mg extended-release tablet with 250 mL commercial grapefruit juice, homogenized grapefruit segments, or extract of segment-free parts equivalent to one unprocessed fruit, or water. Inhibition of recombinant CYP3A4 by furanocoumarins (bergamottin, 6′,7′-epoxybergamottin, and 6′,7′-dihydroxybergamottin) and flavonoids was determined. Felodipine AUC with commercial grapefruit juice, grapefruit segments, or grapefruit extract was on average 3-fold higher than with water. 6′,7′-Dihydroxybergamottin and naringin may be more important in grapefruit segments because they are present in higher concentrations.
Evidence strength assessment: The human clinical evidence for DHB's involvement in the grapefruit juice–felodipine interaction is moderate. Specific studies have been small (5–12 subjects), and their methodology for isolating DHB's contribution from that of other furanocoumarins (bergamottin, paradisins) and flavonoids has varied, leading to conflicting conclusions. The PBPK modeling approach has helped reconcile these discrepancies (see below).
A 1999 clinical study (Edwards et al.) found that the AUC and peak concentration of cyclosporine were increased by 55% and 35%, respectively, with grapefruit juice (p < 0.05). Seville orange juice had no influence on cyclosporine disposition but reduced enterocyte concentrations of CYP3A4 by an average of 40%. 6′,7′-Dihydroxybergamottin did not inhibit P-glycoprotein at concentrations up to 50 μmol/L. Therefore, 6′,7′-dihydroxybergamottin is not responsible for the effects of grapefruit juice on cyclosporine. Because the interaction did not occur with Seville orange juice despite reduced enterocyte CYP3A4, inhibition of P-glycoprotein activity by other compounds in grapefruit juice may be responsible. Reduced enterocyte CYP3A4 by 6′,7′-dihydroxybergamottin could be important for other drugs whose bioavailability is less dependent on P-glycoprotein.
A 2023 study published in Clinical Pharmacology & Therapeutics established a physiologically based pharmacokinetic (PBPK) model using both bergamottin and DHB. The study aimed to establish a physiologically based pharmacokinetic (PBPK) grapefruit-drug interaction model simulating the effect of grapefruit juice consumption on plasma concentration-time profiles of various CYP3A4 victim drugs. The model was developed in PK-Sim and coupled with previously developed PBPK models of CYP3A4 substrates. Overall, 43 clinical studies were used for model development. For example, pronounced increases in felodipine (up to 3.3-fold) and simvastatin (up to 18-fold) in area under the plasma concentration-time curve were observed after grapefruit juice ingestion, which could result in pronounced pharmacodynamic effects.
Effects on CYP3A4 victim drugs can still be measured up to 24 hours after grapefruit juice consumption. This prolonged duration of action reflects the irreversible, mechanism-based nature of CYP3A4 inactivation by DHB; the enzyme must be resynthesized de novo to restore full activity.
Drug categories affected by grapefruit juice (containing furanocoumarins including DHB) include: antihistamines (fexofenadine, terfenadine), anti-infectives (erythromycin, halofantrine, praziquantel), antiretrovirals (saquinavir), cardiovascular drugs (aliskiren, azelnidipine, celiprolol, felodipine, manidipine, nicardipine, nifedipine, nimodipine, nisoldipine, talinolol), central nervous system agents (alfentanil, buspirone, carbamazepine, diazepam, fluvoxamine, methadone, midazolam, phenytoin, sertraline, triazolam), immunosuppressants (cyclosporine, tacrolimus), statins (atorvastatin, lovastatin, simvastatin), and oncology agents (etoposide).
Current evidence level: Preclinical (cell-based) only.
DHB and its metabolites are natural furanocoumarins found principally in grapefruit juice. They have been shown to exert inhibitory effects on cytochrome P450. The question of whether DHB modulates inflammatory responses in RAW 264.7 macrophage cells has been investigated to elucidate its pharmacological and biological effects on the production of proinflammatory cytokines and inflammatory mediators by macrophages. In that study, DHB was found to be an effective inhibitor of LPS-induced nitric oxide and prostaglandin E₂ production in RAW 264.7 cells, and its inhibitory effects included dose-dependent decreases in inducible NO synthase and cyclooxygenase-2 protein expression.
A separate cell-culture study using Kaffir lime-derived DHB confirmed these findings in both macrophage and colon epithelial cell lines. DHB inhibited LPS-interferon-γ-induced NO and iNOS production in RAW264.7 cells and COX-2 production in HT-29 and HCT116 cells with IC₅₀ values of approximately 16–18 μg/mL across assays. No human clinical trials on DHB's anti-inflammatory properties have been published.
Current evidence level: Preclinical (cell-based and animal) only.
Furanocoumarins' defensive and restorative impacts have been observed in leukemia, glioma, breast, lung, renal, liver, colon, cervical, ovarian, and prostate malignancies in experimental settings. Experimental findings have shown that furanocoumarins activate multiple signaling pathways, leading to apoptosis, autophagy, antioxidant activity, antimetastatic effects, and cell cycle arrest in malignant cells. These results are based on in vitro work with various furanocoumarin family members and do not isolate DHB's individual contribution in human or animal models. No clinical trials on DHB as an anticancer agent have been published.
Current evidence level: Mechanistic (in vitro and pharmacokinetic modeling); no dedicated human clinical trials.
6,7-Dihydroxybergamottin is considered an inhibitor of some isoforms of the cytochrome P450 enzyme, particularly CYP3A4. This prevents oxidative metabolism of certain drugs by the enzyme, resulting in an elevated concentration of drug in the bloodstream. Therefore 6,7-dihydroxybergamottin is also sold on the market as an "anabolic amplifier" for increasing the absorption of supplements, drugs, and oral anabolic steroids.
The theoretical basis for this use is the same CYP3A4 inhibition mechanism documented in grapefruit juice–drug interaction research. However, no dedicated human clinical trials have evaluated DHB as a bioavailability enhancer for specific dietary supplements or anabolic compounds at defined doses of isolated DHB. The evidence base for this commercial application is entirely inferred from the grapefruit juice pharmacokinetic literature.
DHB does not have an established therapeutic dose in humans derived from dedicated clinical trials. Dosage information available in the scientific literature pertains to concentrations in grapefruit juice or to amounts used in pharmacokinetic studies:
In the dietary supplement market, DHB is commonly formulated in capsule or tablet form, often combined with other extracts. Specific dosages claimed by manufacturers have not been validated in dedicated human dose-finding studies and are therefore not reported here.
The most significant and well-documented safety concern for DHB is its potential to cause clinically relevant pharmacokinetic drug interactions through irreversible CYP3A4 inactivation. The inhibitory effect is mainly attributed to furanocoumarins irreversibly inhibiting preferably intestinal CYP3A4 as suicide inhibitors. Effects on CYP3A4 victim drugs can still be measured up to 24 hours after grapefruit juice consumption.
Exposure to grapefruit juice can increase the concentration of certain drugs (such as antihistamines, cyclosporine, and statins) in the blood, thus increasing the risk of side effects. This risk is particularly pronounced for older and more vulnerable individuals.
Inhibition of CYP3A4 in the small intestine may elevate drug plasma concentrations (especially felodipine, amiodarone), which increases the risk of adverse reactions (toxicity) of administered drugs. So, 6′,7′-dihydroxybergamottin does not cause side effects per se but can interfere with prescription medications, which may trigger dangerous side effects.
The importance of the interaction appears to be influenced by individual patient susceptibility, type and amount of grapefruit juice, and administration-related factors. The degree of juice-drug interactions can be influenced by the volume of juice consumed, the type and variety of fruit, the time between juice consumption and drug administration, and the polymorphisms in the genes encoding specific enzymes or transporters.
It is important to note that most clinical evidence pertains to whole grapefruit juice — a complex mixture containing bergamottin, DHB, paradisins, epoxybergamottin, flavonoids, and other constituents. Mixing five representative furanocoumarins at their detectable levels in grapefruit juice reproduced roughly the inhibitory potencies of grapefruit juice, but omission of any of the components resulted in decreased potencies. These results suggest that all the major furanocoumarins contributed to the CYP3A inhibitory properties of grapefruit juice. This means that attributing specific drug interaction risks to isolated DHB supplements requires inference from grapefruit juice research, rather than from direct human studies of purified DHB.
Unlike CYP3A4 inhibition (which raises drug plasma concentrations), OATP inhibition reduces uptake of certain drugs. Fruit juices and constituents are more potent inhibitors of OATPs than of P-glycoprotein activities, which can reduce oral drug bioavailability. This supports a new model of intestinal drug absorption and a distinct mechanism of food-drug interaction. This can decrease the therapeutic efficacy of drugs that rely on OATP-mediated uptake (such as fexofenadine), a mechanism distinct from and in the opposite direction to the CYP3A4-mediated effect.
DHB inhibits the in vitro activity of multiple CYP isoforms: CYP1A2, CYP1B1, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. The concentration of 6′,7′-dihydroxybergamottin in grapefruit juice exceeded the IC₅₀ for loss of CYP3A4 activity in vitro. CYP1A1 and CYP2D6 protein content were not affected at the same concentrations in the Caco-2 cell model. The extent to which DHB inhibits these additional CYP isoforms at physiologically achievable concentrations in humans has not been definitively established in controlled clinical studies.
Furanocoumarins as a chemical class are known photosensitizers, capable of forming DNA adducts upon UV light exposure. Exposure to furanocoumarins in large doses combined with ultraviolet radiation, such as through photochemotherapy, is known to induce skin tumorigenesis in both animals and humans. This phototoxic risk, associated with psoralen-type furanocoumarins, has not been specifically and quantitatively characterized for DHB at typical dietary or supplemental exposures; the concern is primarily a theoretical one based on the compound's structural class membership.
As of the available literature, DHB as an isolated supplement ingredient has not been the subject of a formal monograph by the European Medicines Agency (EMA), German Commission E, ESCOP, or the USP. The NIH Office of Dietary Supplements has not published a standalone fact sheet for isolated DHB. Its safety is therefore evaluated inferentially from grapefruit juice pharmacology and from in vitro toxicological data, rather than from the clinical safety database that would accompany a regulated drug substance.
Health conditions that 6,7-dihydroxybergamottin may help support.
Body systems that 6,7-dihydroxybergamottin may help support.
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