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Enantiomers of naringenin as pleiotropic, stereoselective inhibitors of cytochrome P450 isoforms
Author(s) -
Lu Wenjie Jessie,
Ferlito Valentina,
Xu Cong,
Flockhart David Alastair,
Caccamese Salvatore
Publication year - 2011
Publication title -
chirality
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.43
H-Index - 77
eISSN - 1520-636X
pISSN - 0899-0042
DOI - 10.1002/chir.21005
Subject(s) - naringenin , chemistry , cyp2b6 , cyp3a , enantiomer , cytochrome p450 , pharmacology , microsome , enzyme , pharmacokinetics , biochemistry , stereoselectivity , stereochemistry , cyp3a4 , flavonoid , catalysis , medicine , antioxidant
Interactions between naringenin and the cytochrome P450 (CYP) system have been of interest since the first demonstration that grapefruit juice reduced CYP3A activity. The effects of naringenin on other CYP isoforms have been less investigated. In addition , it is well known that interactions with enzymes are often stereospecific, but due to the lack of readily available pure naringenin enantiomers, the enantioselectivity of its effects has not been characterized. We isolated pure naringenin enantiomers by chiral high‐performance liquid chromatography and tested the ability of ( R )‐,( S )‐ and rac ‐naringenin to inhibit several important drug‐metabolizing CYP isoforms using recombinant enzymes and pooled human liver microsomes. Naringenin was able to inhibit CYP19, CYP2C9, and CYP2C19 with IC 50 values below 5 μM. No appreciable inhibition of CYP2B6 or CYP2D6 was observed at concentrations up to 10 μM. Whereas ( S )‐naringenin was 2‐fold more potent as an inhibitor of CYP19 and CYP2C19 than ( R )‐naringenin, ( R )‐naringenin was 2‐fold more potent for CYP2C9 and CYP3A. Chiral flavanones like naringenin are difficult to separate into their enantiomeric forms, but enantioselective effects may be observed that ultimately impact clinical effects. Inhibition of specific drug metabolizing enzymes by naringenin observed in vitro may be exploited to understand pharmacokinetic changes seen in vivo. Chirality, 2011. © 2011 Wiley‐Liss, Inc.