title: Major furocoumarins in grapefruit juice II: phototoxicity, photogenotoxicity, and inhibitory potency vs. cytochrome P450 3A4 activity.
abstract: Furocoumarins are phototoxic and photogenotoxic natural constituents occurring in a broad variety of plants used in cosmetics, food, and drugs. Grapefruit juice is considered as a major dietary source of furocoumarins although very few is known about the phototoxic properties of furocoumarins in grapefruit. Here we analyzed the phototoxicity and photogenotoxicity of the three major furocoumarins previously found in commercial and freshly prepared grapefruit juices, i.e. bergaptol, bergamottin, and 6',7'-dihydroxy bergamottin (DHB). We found that DHB was much less toxic than the reference furocoumarin 5-methoxypsoralen (5-MOP) in V79 cells irradiated with UVA light, while bergamottin and bergaptol were not phototoxic. The photomutagenic potency, tested in the V79 HPRT mutagenicity assay, was found to be in the rank order 5-MOP>>DHB>bergamottin while bergaptol was not photomutagenic. In the V79 micronucleus assay, DHB was about 1/7 as potent as 5-MOP whereas bergaptol and bergamottin were inactive. In a cytochrome P450 3A4 inhibition assay in human liver microsomes, IC50 values of 1.2 μM (DHB), 4.5 μM (bergamottin), and 77.5 μM (bergaptol) were found suggesting that all three furocoumarins contribute to the CYP3A4-inhibitory effect of grapefruit juice. These findings demonstrate that the sum of furocoumarins overestimates the phototoxic properties of grapefruit juice.
authors.affiliation: Food Chemistry and Toxicology, University of Kaiserslautern, D-67663 Kaiserslautern, Germany.
authors.forename: Anastasia
authors.initials: A
authors.lastname: Messer
authors.forename: Nicole
authors.initials: N
authors.lastname: Raquet
authors.forename: Christiane
authors.initials: C
authors.lastname: Lohr
authors.forename: Dieter
authors.initials: D
authors.lastname: Schrenk
mesh_terms: D000818:Animals; D001628:Beverages / Q000032:analysis*; D002460:Cell Line; D032083:Citrus paradisi / Q000737:chemistry*; D006224:Cricetinae; D051544:Cytochrome P-450 CYP3A; D065692:Cytochrome P-450 CYP3A Inhibitors; D011564:Furocoumarins / Q000633:toxicity*; D006801:Humans; D007041:Hypoxanthine Phosphoribosyltransferase / Q000235:genetics; D008862:Microsomes, Liver / Q000201:enzymology; D009152:Mutagenicity Tests; D009153:Mutagens / Q000633:toxicity*; D014466:Ultraviolet Rays
chemical_list: D065692:Cytochrome P-450 CYP3A Inhibitors; D011564:Furocoumarins; D009153:Mutagens; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D007041:Hypoxanthine Phosphoribosyltransferase