Increased steroid absorption by 6′,7′-Dihydroxybergamottin

6′,7′-Dihydroxybergamottin (DHB) is a natural furanocoumarin found mostly in grapefruit juice and Seville orange juice. DHB is believed to be responsible for so-called grapefruit juice effect.

Why is 6′,7′-Dihydroxybergamottin Found in Supplements?

6′,7′-Dihydroxybergamottin is sold as “anabolic amplifier” and is supposed to increase the absorption of supplements, drugs, oral anabolic steroids and even food. DHB was reported to be very effective at inhibiting the cytochrome P450 CYP3A4 enzyme activity in intestine [1] and liver [2,3], which is responsible for decreasing small foreign organic molecule absorption.

Active ingredients (such as 6′,7′-DHB) in grapefruit juice are responsible for greater bioavailability of drugs after oral dosing but not after intravenous administration of the same drugs [4]. It has been shown that 6-beta-hydroxylase activity (exhibited by CYP3A4 enzyme [5]) plays and important role in metabolism of the anabolic steroids [6]. Both in vivo and vitro hydroxylation at 6-beta-position catalyzed by CYP3A4 enzyme was reported for testosterone, progesterone, cortisol and androstenedione, as well as for the synthetic compounds, methandrostenolone (metandienone [trade names Averbol, Dianabol, Danabol, Dbol]), budesonide and dexamethasone [6]. Therefore, many bodybuilders couple their oral anabolics with 6′,7′-DHB and/or bergamottin. In this case, with greater bioavailability comes greater toxicity and adverse reactions (most commonly gynecomastia, high blood pressure, acne and male pattern baldness).

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In 2014 Karen M. VanderMolen et al. [7] analyzed six sports nutrition supplements that were labeled to contain the furanocoumarin(s) bergamottin and/or 6′,7′-dihydroxybergamottin. Contrary to the product labeling, four of the supplements contained no detectable quantities of either furanocoumarin, while two of the supplements contained minimal amounts. CYP3A inhibition by this low amounts of bergamottin and DHB was greater than it could be accounted for by the two furanocoumarins which suggests the presence of other potent or highly abundant CYP3A inhibitors.

What is Grapefruit Juice Effect and is 6′,7′-Dihydroxybergamottin Responsible for it?

Grapefruit juice can increase the oral bioavailability of a broad range of medications [8] as it produces mechanism-based inhibition of intestinal drug metabolism when consumed [9]. As mentioned before 6′,7′-dihydroxybergamottin has been identified as probable active constituent responsible for grapefruit juice effect [10]. However, studies report that it is not the major active ingredient, although it largely contributes to the grapefruit juice-felodipine interaction [10,11]. A study published on Nature.com [12] concluded that grapefruit juice (but not 6′,7′-DHB) increased concentration of cyclosporine probably because intestinal P-glycoprotein may be a more important determinant of cyclosporine availability than inhibition of cytochrome P450 CYP3A4. Studies suggest that grapefruit juice also affects, but only to a minor extent, the modulation of P-glycoprotein function [12,15,16].

6′,7′-Dihydroxybergamottin is an important contributor to grapefruit juice effect [2,1], however grapefruit juice contains many other flavonoids and furanocoumarin derivatives that may alter the metabolism of drugs by CYP [4,13].

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Side Effects and Precautions

Inhibition of the CYP3A4 in the small intestine may elevate drug plasma concentrations (especially felodipine, amiodarone) which increases the risk of adverse reactions (increases the toxicity) of administered drugs [14]. So, 6′,7′-dihydroxybergamottin does not cause side effects per se but it can interfere with prescription medications which may trigger dangerous side effects.

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References

1. Kakar, Shefali M., et al. “6′ 7′-Dihydroxybergamottin Contributes to the Grapefruit Juice Effect*.” Clinical Pharmacology & Therapeutics 75.6 (2004): 569-579.
2. Edwards, David J., F. H. Bellevue, and Patrick M. Woster. “Identification of 6′, 7′-dihydroxybergamottin, a cytochrome P450 inhibitor, in grapefruit juice.” Drug metabolism and disposition 24.12 (1996): 1287-1290.
3. Bellevue III, Frank H., et al. “Synthesis and biological evaluation of 6′, 7′-dihydroxybergamottin (6, 7-DHB), a naturally occurring inhibitor of cytochrome P450 3A4.” Bioorganic & Medicinal Chemistry Letters 7.20 (1997): 2593-2598.
4. Dahan, A., and H. Altman. “Food–drug interaction: grapefruit juice augments drug bioavailability—mechanism, extent and relevance.” European journal of clinical nutrition 58.1 (2004): 1-9.
5. http://www.genecards.org/cgi-bin/carddisp.pl?gene=CYP3A4
6. Rendic, Slobodan, Eckhard Nolteernsting, and Wilhelm Schänzer. “Metabolism of anabolic steroids by recombinant human cytochrome P450 enzymes: Gas chromatographic–mass spectrometric determination of metabolites.” Journal of Chromatography B: Biomedical Sciences and Applications 735.1 (1999): 73-83.
7. VanderMolen, Karen M., et al. “Labeled Content of Two Furanocoumarins in Dietary Supplements Correlates with neither Actual Content nor CYP3A Inhibitory Activity.” Journal of Pharmaceutical and Biomedical Analysis (2014).
8. Dresser, George K., David G. Bailey, and S. George Carruthers. “Grapefruit juice-felodipine interaction in the elderly.” Clinical Pharmacology and Therapeutics-St Louis- 68.1 (2000): 28-34.
9. Dresser, G. K., and D. G. Bailey. “The effects of fruit juices on drug disposition: a new model for drug interactions.” European journal of clinical investigation 33.s2 (2003): 10-16.
10. Bailey, David G., et al. “Grapefruit juice—felodipine interaction: Effect of naringin and 6′, 7′-dihydroxybergamottin in humans*.” Clinical Pharmacology & Therapeutics 64.3 (1998): 248-256.
11. Malhotra, Shefali, et al. “Seville orange juice-felodipine interaction: Comparison with dilute grapefruit juice and involvement of furocoumarins*.” Clinical Pharmacology & Therapeutics 69.1 (2001): 14-23.
12. Edwards, David J., et al. “6′, 7′-Dihydroxybergamottin in grapefruit juice and Seville orange juice: Effects on cyclosporine disposition, enterocyte CYP3A4, and P-glycoprotein*.” Clinical Pharmacology & Therapeutics 65.3 (1999): 237-244.
13. Ho, Ping-Chuen, Dorothy J. Saville, and Sompon Wanwimolruk. “Inhibition of human CYP3A4 activity by grapefruit flavonoids, furanocoumarins and related compounds.” J Pharm Pharm Sci 4.3 (2001): 217-227.
14. Wolters Kluwer Health. “Grapefruit.” Drugs.com
15. Ohnishi, Ayako, et al. “Effect of furanocoumarin derivatives in grapefruit juice on the uptake of vinblastine by Caco‐2 cells and on the activity of cytochrome P450 3A4.” British journal of pharmacology 130.6 (2000): 1369-1377.
16. Eagling, V. A., L. Profit, and D. J. Back. “Inhibition of the CYP3A4-mediated metabolism and P-glycoprotein-mediated transport of the HIV-1 protease inhibitor saquinavir by grapefruit juice components.” British journal of clinical pharmacology 48 (1999): 543-552.
17. Kakar, Shefali M., et al. “6′ 7′-Dihydroxybergamottin Contributes to the Grapefruit Juice Effect*.” Clinical Pharmacology & Therapeutics 75.6 (2004): 569-579.