TY - JOUR
T1 - Risk assessment of the inhibition of hydroxygenkwanin on human and rat cytochrome P450 by cocktail method
AU - Gao, Jing
AU - Zhang, Yuanjin
AU - Lei, Xueqin
AU - Xu, Yuan
AU - Sun, Zhenliang
AU - Wang, Xin
N1 - Publisher Copyright:
© 2021 Elsevier Ltd
PY - 2022/3
Y1 - 2022/3
N2 - Hydroxygenkwanin (HGK), a natural flavonoid extracted from the buds of Daphne genkwa Sieb.et Zucc. (Thymelaeaceae), possesses a wide range of pharmacological activities, including anti-inflammatory, antibacterial and anticancer. However, the inhibitory effect of HGK on cytochrome P450 (CYP) remains unclear. This study investigated the potential inhibitory effects of HGK on CYP1A2, 2B1/6, 2C9/11, 2D1/6, 2E1 and 3A2/4 enzymes in human and rat liver microsomes (HLMs and RLMs) by the cocktail approach. HGK exhibited no time-dependent inhibition of CYP activities in HLMs and RLMs. Enzyme inhibition kinetics indicated that HGK was not only a competitive inhibitor of human CYP1A2 and 2C9, but also competitively inhibited rat CYP1A2 and 2C11 activities, with Ki value at 0.84 ± 0.03, 8.09 ± 0.44, 2.68 ± 0.32 and 8.35 ± 0.31 μM, respectively. Further studies showed that the inhibitory effect of HGK on CYP enzymes was weaker than that of diosmetin, which may be related to the substitution of hydroxyl and methoxy in the A and B rings of the flavone skeleton. Therefore, the low Ki values of HGK for CYP1A2 and 2C may lead to potential drug-drug interactions and toxicity.
AB - Hydroxygenkwanin (HGK), a natural flavonoid extracted from the buds of Daphne genkwa Sieb.et Zucc. (Thymelaeaceae), possesses a wide range of pharmacological activities, including anti-inflammatory, antibacterial and anticancer. However, the inhibitory effect of HGK on cytochrome P450 (CYP) remains unclear. This study investigated the potential inhibitory effects of HGK on CYP1A2, 2B1/6, 2C9/11, 2D1/6, 2E1 and 3A2/4 enzymes in human and rat liver microsomes (HLMs and RLMs) by the cocktail approach. HGK exhibited no time-dependent inhibition of CYP activities in HLMs and RLMs. Enzyme inhibition kinetics indicated that HGK was not only a competitive inhibitor of human CYP1A2 and 2C9, but also competitively inhibited rat CYP1A2 and 2C11 activities, with Ki value at 0.84 ± 0.03, 8.09 ± 0.44, 2.68 ± 0.32 and 8.35 ± 0.31 μM, respectively. Further studies showed that the inhibitory effect of HGK on CYP enzymes was weaker than that of diosmetin, which may be related to the substitution of hydroxyl and methoxy in the A and B rings of the flavone skeleton. Therefore, the low Ki values of HGK for CYP1A2 and 2C may lead to potential drug-drug interactions and toxicity.
KW - Bupropion (PubChem CID: 444).
KW - Chlorzoxazone (PubChem CID: 2733).
KW - Cocktail approach
KW - Cytochrome P450 (CYP)
KW - Dextromethorphan (PubChem CID: 5360696).
KW - Diosmetin
KW - Diosmetin (PubChem CID: 5281612).
KW - Drug-drug interactions
KW - Hydroxygenkwanin
KW - Hydroxygenkwanin (PubChem CID: 5318214).
KW - Midazolam (PubChem CID: 4192).
KW - Phenacetin (PubChem CID: 4754)
KW - Tolbutamide (PubChem CID: 5505).
UR - https://www.scopus.com/pages/publications/85120749278
U2 - 10.1016/j.tiv.2021.105281
DO - 10.1016/j.tiv.2021.105281
M3 - 文章
C2 - 34843882
AN - SCOPUS:85120749278
SN - 0887-2333
VL - 79
JO - Toxicology in Vitro
JF - Toxicology in Vitro
M1 - 105281
ER -