6,7-dihydroxy Bergamottin

IC50: 25 μM

6,7-dihydroxy Bergamottin, also known as 6,7-DHB, is a potent inhibitor of cytochrome P4503A4 (CYP3A4) with an IC50 value of 25 μM. As a primary compound in grapefruit juice, 6,7-DHB is responsible for the blockade the activity of testosterone 6β-hydrolase.

CYP3A4 is an important enzyme, mainly found in both the intestinal wall and liver, which oxidizes small foreign organic molecules (xenobiotics), such as toxins or drugs.

In vitro: 6,7-DHB significantly blocked the testosterone 6β-hydrolase in human liver microsomes and human CYP3A4 expressed in Escherichia coli membrane in a time- and concentration-dependent manner. Furthermore, 6,7-DHB proved to be a potent NADPH- and time-dependent inhibitor of CYP3A4 [1]. 6,7-DHB concentration-dependently inhibited nifedipine (NFP) oxidation in HepG2-GS-3A4 cell, a cell line from hepatoblastoma with overexpression of human CYP3A4 [2].

In vivo: Male Wistar-ST rats were intraduodenally administered with 6,7-DHB at a dose of 3.4 mg/ml. After 4 hours, 6,7-DHB had no significant effects on the NFP plasma concentrations, suggesting that 6,7-DHB had no pharmacokinetic effect on the rats [3].

References:
[1].  Bellevue, F., Woster, P., Edwards, D., He, K., & Hollenberg, P. Synthesis and biological evaluation of 6′,7′-dihydroxybergamottin (6,7-DHB), a naturally occurring inhibitor of cytochrome P450 3A4. Bioorganic & Medicinal Chemistry Letters. 1997; 7(20): 2593-2598.
[2].  Araki, N., Tsuruoka, S., Hasegawa, G., Yanagihara, H., Omasa, T., & Enosawa, S. et al. Inhibition of CYP3A4 by 6′,7′-dihydroxybergamottin in human CYP3A4 over-expressed hepG2 cells. Journal of Pharmacy and Pharmacology. 2012; 64(12): 1715-1721.
[3].  Mohri, K., & Uesawa, Y. Effects of Furanocoumarin Derivatives in Grapefruit Juice on Nifedipine Pharmacokinetics in Rats. Pharmaceutical Research, 2001;18(2):177-182.