Specific CYP3A4 inhibitors in grapefruit juice: furocoumarin dimers as components of drug interaction

Pharmacogenetics. 1997 Oct;7(5):391-6. doi: 10.1097/00008571-199710000-00008.


Four components were isolated from grapefruit juice that inhibit human CYP3A-mediated drug oxidation. The structures of these compounds were identified as furocoumarin derivatives by absorption spectra, APCI-liquid chromatography/tandem mass spectrometry and nuclear magnetic resonance after their purification by reversed-phase high performance liquid chromatography. They include two new furocoumarins, 4-[[6-hydroxy-7-[[1-[(1-hydroxy-1-methyl)ethyl]-4-methyl-6- (7-oxo-7H-furo[3,2-g][1]benzopyran-4-yl)-4-hexenyl]oxy]-3,7-dimeth yl- 2-octenyl] oxy]-7H-furo[3,2-g][1]benzopyran-7-one (GF-I-1) and 4-[[6-hydroxy-7-[[4-methyl-I- (1-methylethenyl)-6-(7-oxo-7H-furo[3,2-g][1]benzopyran-4-yl)-4- hexenyl] oxy]-3,7-dimethyl-2-octenyl]oxy]-7H-furo[3,2-g][1]benzopyran-7-one (GF-I-4). These furocoumarins are strong candidates for causative agents of grapefruit juice-mediated drug interaction, because of an inhibition potential that is equal to or stronger than the prototypical CYP3A4 inhibitor, ketoconazole, on liver microsomal testosterone 6 beta-hydroxylation.

MeSH terms

  • Beverages
  • Chromatography, High Pressure Liquid
  • Citrus / chemistry*
  • Cytochrome P-450 CYP3A
  • Cytochrome P-450 Enzyme Inhibitors*
  • Dimerization
  • Drug Interactions
  • Enzyme Inhibitors / pharmacology*
  • Furocoumarins / chemistry
  • Furocoumarins / pharmacology*
  • Humans
  • Hydroxylation
  • Microsomes, Liver / metabolism
  • Mixed Function Oxygenases / antagonists & inhibitors*
  • Spectrum Analysis
  • Testosterone / metabolism


  • Cytochrome P-450 Enzyme Inhibitors
  • Enzyme Inhibitors
  • Furocoumarins
  • Testosterone
  • Mixed Function Oxygenases
  • CYP3A protein, human
  • Cytochrome P-450 CYP3A
  • CYP3A4 protein, human