Inhibition of human CYP3A4 activity by grapefruit flavonoids, furanocoumarins and related compounds

J Pharm Pharm Sci. Sep-Dec 2001;4(3):217-27.

Abstract

Purpose: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Beverages
  • Citrus*
  • Coumarins / pharmacology*
  • Cytochrome P-450 CYP3A
  • Cytochrome P-450 Enzyme Inhibitors*
  • Enzyme Activation / drug effects
  • Enzyme Inhibitors / pharmacology
  • Flavonoids / pharmacology*
  • Furans / pharmacology*
  • Humans
  • Microsomes, Liver / drug effects
  • Microsomes, Liver / enzymology
  • Mixed Function Oxygenases / antagonists & inhibitors*
  • Plant Extracts / pharmacology

Substances

  • Coumarins
  • Cytochrome P-450 Enzyme Inhibitors
  • Enzyme Inhibitors
  • Flavonoids
  • Furans
  • Plant Extracts
  • Mixed Function Oxygenases
  • CYP3A protein, human
  • Cytochrome P-450 CYP3A
  • CYP3A4 protein, human