title: In Vitro and in Vivo Inhibitory Effects of Glycyrrhetinic Acid in Mice and Human Cytochrome P450 3A4.
abstract: Glycyrrhetinic acid (GA) has been used clinically in the treatment of patients with chronic hepatitis. This study evaluated the effect of GA on the activity of five P450(CYP450) cytochrome enzymes: CYP2A6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4, in human liver microsomes (HLMs) and recombinant cDNA-expressed enzyme systems using a HPLC-MS/MS CYP-specific probe substrate assay. With midazolam as the probe substrate, GA greatly decreased CYP3A4 activity with IC50 values of 8.195 μM in HLMs and 7.498 μM in the recombinant cDNA-expressed CYP3A4 enzyme system, respectively. It significantly decreased CYP3A4 activity in a dose- but not time-dependent manner. Results from Lineweaver-Burk plots showed that GA could inhibit CYP3A4 activity competitively, with a Ki value of 1.57 μM in HLMs. Moreover, CYP2C9 and CYP2C19 could also be inhibited significantly by GA with IC50 of 42.89 and 40.26 μM in HLMs, respectively. Other CYP450 isoforms were not markedly affected by GA. The inhibition was also confirmed by an in vivo study of mice. In addition, it was observed that mRNA expressions of the Cyps2c and 3a family decreased significantly in the livers of mice treated with GA. In conclusion, this study indicates that GA may exert herb-drug interactions by competitively inhibiting CYP3A4.
authors.affiliation: Department of Clinical Pharmacology, Xiangya Hospital; Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Central South University, Changsha 410008, China. lvqiaoli2008@126.com.
authors.forename: Qiao-Li
authors.initials: QL
authors.lastname: Lv
authors.affiliation: Department of Oncology, Changsha Central Hospital, Changsha 410006, China. wangguihua2008@126.com.
authors.forename: Gui-Hua
authors.initials: GH
authors.lastname: Wang
authors.affiliation: Department of Oncology, Changsha Central Hospital, Changsha 410006, China. chenshuhui2008@126.com.
authors.forename: Shu-Hui
authors.initials: SH
authors.lastname: Chen
authors.affiliation: Department of Clinical Pharmacology, Xiangya Hospital; Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Central South University, Changsha 410008, China. zhuifenglang@163.com.
authors.forename: Lei
authors.initials: L
authors.lastname: Hu
authors.affiliation: Department of Clinical Pharmacology, Xiangya Hospital; Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Central South University, Changsha 410008, China. zhangx2013cs@163.com.
authors.forename: Xue
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Clinical Pharmacology, Xiangya Hospital; Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Central South University, Changsha 410008, China. guoying198688@126.com.
authors.forename: Guo
authors.initials: G
authors.lastname: Ying
authors.affiliation: Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China. qcz0378@126.com.
authors.forename: Chong-Zhen
authors.initials: CZ
authors.lastname: Qin
authors.affiliation: Department of Clinical Pharmacology, Xiangya Hospital; Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Central South University, Changsha 410008, China. hhzhou2003@163.com.
authors.forename: Hong-Hao
authors.initials: HH
authors.lastname: Zhou
mesh_terms: D000818:Animals; D002478:Cells, Cultured / Q000187:drug effects*; D051544:Cytochrome P-450 CYP3A / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000378:metabolism*; D006034:Glycyrrhetinic Acid / Q000378:metabolism* / Q000627:therapeutic use; D006521:Hepatitis, Chronic / Q000188:drug therapy*; D041743:Herb-Drug Interactions; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008862:Microsomes, Liver / Q000378:metabolism*; D010936:Plant Extracts / Q000378:metabolism* / Q000627:therapeutic use; D053719:Tandem Mass Spectrometry
chemical_list: D004791:Enzyme Inhibitors; D010936:Plant Extracts; D051544:Cytochrome P-450 CYP3A; D006034:Glycyrrhetinic Acid
keywords: IC50; cytochrome P450 3A4; glycyrrhetinic acid; herb–drug interaction; inhibitory effect