Mechanism-based inhibition of human cytochrome P450-3A activity by grapefruit hybrids having low furanocoumarin content.
A citrus breeding program aimed at developing low furanocoumarin (FC) grapefruit cultivars provided 40 grapefruit juice (GFJ) samples containing variable concentrations of FC derivatives, established as being mechanism-based (irreversible) inhibitors of human CYP3A isoforms.        The principal inhibitory FCs were identified as 6',7'-dihydroxybergamottin, along with a series of dimeric compounds (spiroesters) having high inhibitory potency.        A random subset of the GFJ samples (n = 25) were tested as CYP3A inhibitors using an in vitro model based on human liver microsomal metabolism of the index substrate triazolam. The reciprocal values of in vitro 50% inhibitory concentrations (IC(50)) were highly correlated with concentrations of inhibitory FCs in the GFJ samples (r(2) = 0.96). However the correlations were driven mainly by a few samples having high FC content and high reciprocal IC(50) (corresponding to low IC(50)). Among the rest of the samples, the relationship was less robust.        Further study is needed to determine how low the FC content needs to be (or how high the IC(50) needs to be) to assure minimal risk of clinical interactions involving GFJ and CYP3A substrate drugs.
Sackler Program in Pharmacology and Experimental Therapeutics, Department of Molecular Physiology and Pharmacology, Tufts University School of Medicine and Tufts Medical Center, Boston, MA 02111, USA. dj.greenblatt@tufts.edu
David J
DJ
Greenblatt
Yanli
Y
Zhao
Michael J
MJ
Hanley
Chunxian
C
Chen
Jerold S
JS
Harmatz
Paul F
PF
Cancalon
Frederick G
FG
Gmitter
D001628:Beverages / Q000032:analysis; D032083:Citrus paradisi / Q000737:chemistry*; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D065692:Cytochrome P-450 CYP3A Inhibitors; D011564:Furocoumarins / Q000494:pharmacology*; D006801:Humans; D006824:Hybridization, Genetic; D006900:Hydroxylation / Q000187:drug effects; D020128:Inhibitory Concentration 50; D007654:Ketoconazole / Q000494:pharmacology; D014229:Triazolam / Q000378:metabolism
D065692:Cytochrome P-450 CYP3A Inhibitors; D011564:Furocoumarins; D014229:Triazolam; D051544:Cytochrome P-450 CYP3A; D007654:Ketoconazole; C104774:6',7'-dihydroxybergamottin