Inhibitory effects of Aegle marmelos and its constituents on CYP3A4 and CYP1A2 in human liver microsomes

Aegle marmelos (bael) is a popular tree in India and other southeast Asian countries, the fruits of which are usually consumed as fresh, dried or juice and are known for their high nutritional value and health benefits. Despite the edible nature of the fruit and therapeutic properties of the tree, no literature is available regarding its potential for drug interactions. Accordingly, this study was aimed to evaluate the effects of bael fruit extract and its constituents to inhibit major drug metabolizing Cytochrome P450 enzymes (CYPs). To accomplish this goal, pooled human liver microsomes (HLM) were utilized. A methanolic extract of Aegle marmelos and three of its furanocoumarins (marmelosin, marmesinin, and 8-hydroxypsoralen) and one alkaloid (aegeline) were tested. The methanolic extract competitively inhibited CYP3A4 (IC50= 5 µg/mL) with an inhibition constant (Ki) of 3.4 µg/mL while a non-competitive inhibition of CYP1A2 (IC50= 0.8 µg/mL; Ki =0.5 µg/mL) was observed. Marmelosin was the most potent inhibitor of both CYP3A4 and 1A2 with IC50 of 2.4µM and 0.2µM, respectively. Similar to the extract, marmelosin was a competitive inhibitor (Ki =0.9µM) of CYP3A4 and non-competitive inhibitor (Ki =0.3µM) of CYP1A2. Marmesinin showed a moderate inhibition of CYP3A4 (IC50= 29µM; Ki =23µM) while no inhibition of CYP1A2 was seen. Aegeline was a very weak inhibitor of CYP3A4 (IC50= 76µM) and showed no inhibition of CYP1A2. In conclusion, strong inhibition of CYP3A4 and 1A2 by bael extract and one of its constituents, marmelosin could result in potential herb-drug interactions and further in vivo studies are warranted in combination with drugs that are substrates of CYP3A4 and 1A2.