New grapefruit cultivars exhibit low cytochrome P4503A4-Inhibition activity. (March 2020)

• Record Type: Journal Article
• Authors: Guttman, Yelena; Yedidia, Iris; Nudel, Adi; Zhmykhova, Yuliya; Kerem, Zohar; Carmi, Nir
• Is Part Of: Food and chemical toxicology. Volume 137(2020)
• Publication Date: 2020-03
• Subjects: Grapefruit juice -- CYP3A4 -- Food–drug interactions -- Furanocoumarins -- Docking; Toxicology -- Periodicals; Food poisoning -- Periodicals; Food Poisoning -- Periodicals; Toxicology -- Periodicals; Toxicologie -- Périodiques; Intoxications alimentaires -- Périodiques; Food poisoning; Toxicology; Periodicals; Electronic journals; 615.9
• DOI: 10.1016/j.fct.2020.111135
• Languages: English
• ISSNs: 0278-6915

Abstract

Abstract: Furanocoumarins are the main compounds responsible for the food–drug interactions known as the grapefruit effect, which is caused by the inhibition of CYP3A4-mediated drug metabolism. We evaluated the effects of two new, low-furanocoumarin grapefruit cultivars on CYP3A4 activity and the roles of different furanocoumarins, individually and together with other juice compounds, in the inhibition of CYP3A4 by grapefruit. Whereas a standard grapefruit cultivar inhibited CYP3A4 activity in a dose-dependent manner, neither of the two examined low-furanocoumarin cultivars had an inhibitory effect. Despite the fact that bergamottin and 6′, 7′-dihydroxybergamottin are weak inhibitors of CYP3A4, their relatively high levels in grapefruit make them the leading cause of the grapefruit effect. We found that furanocoumarins together with other juice compounds inhibit CYP3A4 in an additive manner. In silico docking simulation was employed, and differentiated between high- and low-potency inhibitors, suggesting that modeling may be useful for identifying potentially harmful food–drug interactions. Highlights: Furanocoumarins in grapefruits cause food-drug interactions by inhibition of CYP3A4. Bergamottin and DHB are the main compounds responsible for the 'grapefruit effect'. New low-furanocoumarin grapefruit cultivars do not inhibit CYP3A4 enzymatic activity. Furanocoumarins with other juice compounds have an additive effect of CYP3A4 inhibition. Docking simulation differentiated between high- and low-potency CYP3A4 inhibitors.