TY - JOUR
T1 - Analysis of inhibition kinetics of three beverage ingredients, bergamottin, dihydroxybergamottin and resveratrol, on CYP2C9 activity
AU - Akiyoshi, Takeshi
AU - Uchiyama, Marika
AU - Inada, Rino
AU - Imaoka, Ayuko
AU - Ohtani, Hisakazu
N1 - Funding Information:
This study was supported in part by the Japan Research Foundation for JSPS Kakenhi (Grant Number 18K06758 ).
Publisher Copyright:
© 2021 The Japanese Society for the Study of Xenobiotics
PY - 2022/2
Y1 - 2022/2
N2 - Some grapefruit juice (GFJ) ingredients and resveratrol, a fruit-derived phytoalexin, are known to inhibit cytochrome P450 (CYP) 2C9. However, their inhibition modes and detailed inhibition kinetics remain undetermined. This study aimed to investigate the inhibitory effects of two GFJ ingredients, bergamottin (BG) and dihydroxybergamottin (DHB), and resveratrol on CYP2C9 activity in vitro. DHB inhibited CYP2C9 activity, as assessed by warfarin 7-hydroxylation, in a preincubation time-dependent manner (i.e., mechanism-based inhibition; MBI), in the same manner as CYP2C19 and CYP3A4. The maximal inactivation rate (kinact,max) was 0.0638 min−1 and 0.12- and 0.26-fold of that for CYP2C19 and CYP3A4, respectively. BG showed both MBI and time-independent competitive inhibition. Resveratrol showed non-competitive inhibition with an inhibition constant (Ki) of 3.64 μM. Unlike the inhibition of CYP2C19 and CYP3A4, resveratrol did not induce MBI. These findings are important for estimating the risk of drug interactions between CYP2C9 substrates and some beverages.
AB - Some grapefruit juice (GFJ) ingredients and resveratrol, a fruit-derived phytoalexin, are known to inhibit cytochrome P450 (CYP) 2C9. However, their inhibition modes and detailed inhibition kinetics remain undetermined. This study aimed to investigate the inhibitory effects of two GFJ ingredients, bergamottin (BG) and dihydroxybergamottin (DHB), and resveratrol on CYP2C9 activity in vitro. DHB inhibited CYP2C9 activity, as assessed by warfarin 7-hydroxylation, in a preincubation time-dependent manner (i.e., mechanism-based inhibition; MBI), in the same manner as CYP2C19 and CYP3A4. The maximal inactivation rate (kinact,max) was 0.0638 min−1 and 0.12- and 0.26-fold of that for CYP2C19 and CYP3A4, respectively. BG showed both MBI and time-independent competitive inhibition. Resveratrol showed non-competitive inhibition with an inhibition constant (Ki) of 3.64 μM. Unlike the inhibition of CYP2C19 and CYP3A4, resveratrol did not induce MBI. These findings are important for estimating the risk of drug interactions between CYP2C9 substrates and some beverages.
KW - Fruit components
KW - Grapefruit juice
KW - Mechanism-based inhibition
KW - Noncompetitive-inhibition
KW - Time-dependent inhibition
KW - Warfarin
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U2 - 10.1016/j.dmpk.2021.100429
DO - 10.1016/j.dmpk.2021.100429
M3 - Article
C2 - 34979453
AN - SCOPUS:85121976329
SN - 1347-4367
VL - 42
JO - Drug Metabolism And Pharmacokinetics
JF - Drug Metabolism And Pharmacokinetics
M1 - 100429
ER -