Abstract
Bioactive furocoumarins present in grapefruit juice are known to increase the bioavailability of certain medications by acting as potent CYP3A4 inhibitors. Furocoumarins were isolated and characterized using a combination of chromatographic techniques. Grapefruit juice was extracted with ethyl acetate and the crude extract was fractionated using silica gel column chromatography. The semi purified fraction was subjected to preparative HPLC to obtain three bioactive furocoumarins. The purity of the isolated compounds was analyzed by analytical HPLC and the structures of these bioactive compounds were confirmed using NMR and mass spectra as bergamottin, 6′, 7′-dihydroxybergamottin (DHB) and paradisin A. The identified compounds were tested for their inhibitory effects on human CYP 3A4 and CYP 1B1 microsomes using specific substrates like dibenzylfluorescein and alkoxyresorufin. Paradisin A was found to be a potent CYP 3A4 inhibitor with an IC50 of 1.12 μM followed by DHB and bergamottin. All the three compounds showed a marked inhibitory effect on CYP 3A4 below 10 μM. Inhibitory effects on CYP 1B1 exhibited a greater variation due to the specificity of substrates, paradisin A showed an IC50 of 3.56 μM for the ethoxy resorufin O-dealkylase (EROD) activity and 33.56 μM for the methoxy resorfin O-dealkylase (MROD) activity. DHB also showed significant variation for EROD and BROD activity, where as bergamottin showed an IC50 of 7.17 μM and 13.86 μM for ethoxy and methoxy substartes, respectively.
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