Inhibitory effect of flavonoids from Scutellariae Radix on human cytochrome P450 1A.
10.19540/j.cnki.cjcmm.20181128.005
- Author:
Dong-Zhu TU
1
;
Hong-Ying MA
2
;
Ya-Qiao WANG
2
;
Xiao-Hua ZHAO
2
;
Wen-Zhi GUO
3
;
Guang-Bo GE
2
;
Ling YANG
2
Author Information
1. Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine Shanghai 201210, China Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital of Zhengzhou University, Henan Key Laboratory of Digestive Organ Transplantation, Zhengzhou Key Laboratory of Hepatobiliary &Pancreatic Diseases and Organ Transplantation, Open and Key Laboratory of Hepatobiliary & Pancreatic Surgery and Digestive Organ Transplantation at Henan Universities Zhengzhou 450001, China.
2. Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine Shanghai 201210, China.
3. Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital of Zhengzhou University, Henan Key Laboratory of Digestive Organ Transplantation, Zhengzhou Key Laboratory of Hepatobiliary &Pancreatic Diseases and Organ Transplantation, Open and Key Laboratory of Hepatobiliary & Pancreatic Surgery and Digestive Organ Transplantation at Henan Universities Zhengzhou 450001, China.
- Publication Type:Journal Article
- Keywords:
CYP1A;
Scutellariae Radix;
flavonoids;
inhibition;
wogonin
- MeSH:
Chromatography, Liquid;
Cytochrome P-450 CYP1A1;
antagonists & inhibitors;
Cytochrome P-450 Enzyme Inhibitors;
pharmacology;
Flavanones;
pharmacology;
Flavonoids;
pharmacology;
Humans;
Molecular Docking Simulation;
Scutellaria baicalensis;
chemistry
- From:
China Journal of Chinese Materia Medica
2019;44(3):566-573
- CountryChina
- Language:Chinese
-
Abstract:
This study investigated the inhibitory effect of eight natural flavonoids in Chinese herb Scutellariae Radix on huamn cytochrome P450 1 A(CYP1 A), a key cancer chemo-preventive target. In this study, phenacetin was used as a probe substrate for CYP1 A, while human liver microsomes and recombinant human CYP1 A enzymes were used as enzyme sources. Liquid chromatography-tandem mass spectrometry was used to monitor the formation rates of acetaminophen, the O-deethylated metabolite of phenacetin. The dose-dependent inhibition curves were depicted based on the changes of the formation rates of acetaminophen, while the IC_(50) were determined. Inhibition kinetic analyses and docking simulations were used to investigate the inhibition modes and mechanism of wogonin(the most potent CYP1 A inhibitor in this herb), while the inhibition constants(K_i) of wogonin against both CYP1 A1 and CYP1 A2 were determined. Among all tested flavonoids, wogonin, 7-methoxyflavanone and oroxylin A displayed a strong inhibitory effect on CYP1 A(IC_(50)<1 μmol·L~(-1)), baicalein exhibited a moderate inhibitory effect on CYP1 A(IC_(50) between 1-10 μmol·L~(-1)), and baicalin, scutellarein and wogonoside displayed a very weak inhibitory effect on CYP1 A(IC_(50) between 10-25 μmol·L~(-1)), but scutellarin displayed a negligible inhibitory effect on CYP1 A(IC_(50)>100 μmol·L~(-1)). Further investigations demonstrated that wogonin had a weak inhibitory effect on other human CYP enzymes, suggesting that it could be used as a lead compound for the development of specific inhibitors of CYP1 A. Furthermore, the inhibition kinetic analyses clearly demonstrated that wogonin could strongly inhibit phenacetin O-deethylation in both CYP1 A1 and CYP1 A2 in a competitive manner, with K_i values at 0.118 and 0.262 μmol·L~(-1), respectively. Molecular docking demonstrated that wogonin could strongly interact with CYP1 A1 and CYP1 A2 via hydrophobic and π-π interactions, as well as Ser120 and Ser116 in CYP1 A1 via hydrogen-bonding. In conclusion, this study found that some flavonoids in Scutellariae Radix displayed a strong inhibitory effect on CYP1 A, while wogonin is the most potent CYP1 A inhibitor with a relatively high selectivity towards CYP1 A over other human CYPs.
