Major furocoumarins in grapefruit juice II: Phototoxicity, photogenotoxicity, and inhibitory potency vs. cytochrome P450 3A4 activity

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.

► We analyzed phototoxicity/-genotoxicity of grapefruit furocoumarins in V79 cells. ► DHB was less phototoxic than 5-MOP; bergamottin and bergaptol were not phototoxic. ► Photomutagenicity order was 5-MOP >> DHB > bergamottin; bergaptol was negative. ► Micronucleus induction order was 5-MOP >> DHB; the others were inactive. ► In CYP inhibition, IC50 values were determined for DHB, bergamottin and bergaptol.