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Title: Inhibition of CYP3A4 and CYP1A2 b Aegle marmelos and its constituents

Author
item MANDA, VAMSHI - University Of Mississippi
item AVULA, BHARATHI - University Of Mississippi
item CHITTIBOYINA, AMAR - University Of Mississippi
item KHAN, IKHLAS - University Of Mississippi
item WALKER, LARRY - University Of Mississippi
item KHAN, SHABANA - University Of Mississippi

Submitted to: Xenobiotica
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 5/16/2015
Publication Date: 8/6/2015
Publication URL: http://handle.nal.usda.gov/10113/62586
Citation: Manda, V.K., Avula, B., Chittiboyina, A.G., Khan, I.A., Walker, L.A., Khan, S.I. 2015. Inhibition of CYP3A4 and CYP1A2 b Aegle marmelos and its constituents. Xenobiotica. 46(2):1366-5928. DOI: 10.3109/00498254.2015.1053006

Interpretive Summary: Aegle marmelos Corr., (Rutaceae family) commonly termed as bael is a popular medicinal tree in India and other Southeast Asian countries. Its fruits are widely consumed as juice or dried form and is reported to be beneficial in treating various ailments. Despite its widespread use, no information is there in the literature regarding its safety information specifically when taken in combination with conventional medications. The current study was aimed to study the effects of bael fruit and its constituents on the main liver metabolic enzymes (Cytochrome P450). Our study showed that bael fruit has a high risk of causing interactions with drugs that are metabolized by liver.

Technical Abstract: Aegle marmelos (bael) is a popular tree in India and other Southeast Asian countries. The fruit is usually consumed as dried, fresh or juice and is reported to have a high nutritional value and many perceived health benefits. Despite of the edible nature and therapeutic properties of A. marmelos, no studies are reported regarding its effects on major drug metabolizing enzymes. This study was aimed to evaluate the inhibitory potential of methanolic extract of A. marmelos fruit and its constituents (3 furanocoumarins namely marmelosin, marmesinin, and 8-hydroxypsoralen and 1 alkaloid, aegeline) towards major Cytochrome P450 enzymes (CYP3A4, 2D6, 1A2, 2C9 and 2C19) using human liver microsomes and recombinant CYPs. The methanolic extract and marmelosin were found to be competitive and time-dependant inhibitors of CYP3A4. While reversible and non-competitive inhibition of CYP1A2 was seen. Time dependent inhibition of CYP3A4 was not affected by the addition of reduced glutathione. Marmesinin showed moderate inhibition of CYP3A4 and 1A2, while aegeline was a very weak inhibitor of CYP3A4 and showed no inhibition for CYP1A2 isoform. No significant inhibition of recombinant CYP2D6, 2C9, and 2C19 was seen with the extract or its constituents. This is the first report of CYP3A4 and 1A2 inhibition by A. marmelos extract and one of its furanocoumarins, marmelosin. Further studies are warranted to determine if acute or prolonged use of bael fruit could affect the pharmacokinetics of drugs that are substrates of CYP3A4 or CYP1A2.