Inhibition of human CYP3A4 activity by grapefruit flavonoids, furanocoumarins and related compounds.
OBJECTIVE
To evaluate the inhibition of CYP3A4 activity in human liver microsomes by flavonoids, furanocoumarins and related compounds and investigate possibly more important and potential inhibitors of CYP3A4 in grapefruit juice.


METHODS
The effects of various flavonoids and furanocoumarin derivatives on CYP3A4 activity in two human liver microsomal samples was determined using quinine as a substrate. All flavonoids and furanocoumarin derivatives were dissolved in DMSO. In all cases, inhibition activities were compared with activities in control incubations containing 0.2% (v/v) DMSO.


RESULTS
The results showed that the inhibition of quinine 3-hydroxylation (CYP3A4 activity) by bergapten (67%), and quercetin (55%) was greater than naringenin (39%) and naringin (6%), at the same inhibitor concentration of 100 M. The results also demonstrated that the furan ring in the furanocoumarins enhanced the inhibitory effect on CYP3A4 activity. Flavonoids with more phenolic hydroxyl (-OH) groups produced stronger inhibition than those with less hydroxyl groups. Of all the chemicals studied, bergapten (5-methoxypsoralen) with the lowest IC50 value (19-36 microM) was the most potent CYP3A4 inhibitor.


CONCLUSIONS
These results suggest that more than one component present in grapefruit juice may contribute to the inhibitory effect on CYP3A4. Bergapten appears to be a potent inhibitor of CYP3A4, and may therefore be primarily responsible for the effect of grapefruit juice on CYP3A4 activity.
Ho
P C
PC
School of Pharmacy, University of Otago, Dunedin, New Zealand.
Saville
D J
DJ
Wanwimolruk
S
S
D001628:Beverages; D002957:Citrus; D003374:Coumarins / Q000494:pharmacology*; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology*; D005663:Furans / Q000494:pharmacology*; D006801:Humans; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors*; D010936:Plant Extracts / Q000494:pharmacology
D003374:Coumarins; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D005419:Flavonoids; D005663:Furans; D010936:Plant Extracts; D006899:Mixed Function Oxygenases; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human