Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association · 2026
Inhibitory properties of grapefruit juice components on human cytochrome P450 3A5 activity.
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Sakamoto Yu, Koinuma Kana, Imaoka Ayuko, Nakamura Katsunori, Yamazaki Hiroshi, Akiyoshi Takeshi, Ohtani Hisakazu
Аннотация
PURPOSE: Grapefruit juice (GFJ) evokes food-drug interactions (FDIs) via mechanism-based inhibition (MBI) of gastrointestinal cytochrome P450 (CYP) 3A4. Bergamottin (BG) and 6',7'-dihydroxybergamottin (DHB) are the primary constituents responsible for this inhibition. Although CYP3A4 and CYP3A5 share overlapping substrate specificity, their inhibitor sensitivity can differ. While BG is a known mechanism-based inhibitor of CYP3A5, the inhibitory property of DHB on the CYP3A5 remains uncharacterized. This study aimed to characterize the inhibitory kinetics of DHB and BG on CYP3A5 metabolic activity in vitro.
METHODS: Recombinant CYP3A5 activity was determined by 1'-hydroxylation of midazolam (MDZ). The concentration of 1'-hydroxymidazolam (1'-OH MDZ) was quantified using LC-MS/MS. The residual intestinal CYP3A5 activity following the ingestion of 200 mL GFJ was estimated using the obtained MBI parameters, kinact,max and KI, and the concentrations of DHB and BG in GFJ.
RESULTS: and Discussion: Both DHB and BG inhibited MDZ 1'-hydroxylation in a concentration- and preincubation time-dependent manner, confirming MBI of CYP3A5. DHB exhibited more potent inhibition than BG, with a kinact,max of 0.20 min-1 and KI of 2.4 μM. These findings suggest that GFJ-mediated FDIs may involve the concurrent inhibition of CYP3A5 alongside CYP3A4, primarily by DHB.
METHODS: Recombinant CYP3A5 activity was determined by 1'-hydroxylation of midazolam (MDZ). The concentration of 1'-hydroxymidazolam (1'-OH MDZ) was quantified using LC-MS/MS. The residual intestinal CYP3A5 activity following the ingestion of 200 mL GFJ was estimated using the obtained MBI parameters, kinact,max and KI, and the concentrations of DHB and BG in GFJ.
RESULTS: and Discussion: Both DHB and BG inhibited MDZ 1'-hydroxylation in a concentration- and preincubation time-dependent manner, confirming MBI of CYP3A5. DHB exhibited more potent inhibition than BG, with a kinact,max of 0.20 min-1 and KI of 2.4 μM. These findings suggest that GFJ-mediated FDIs may involve the concurrent inhibition of CYP3A5 alongside CYP3A4, primarily by DHB.