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Int. J. Environ. Res. Public Health 2016, 13(1), 84; doi:10.3390/ijerph13010084

In Vitro and in Vivo Inhibitory Effects of Glycyrrhetinic Acid in Mice and Human Cytochrome P450 3A4

Department of Clinical Pharmacology, Xiangya Hospital; Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Central South University, Changsha 410008, China
Department of Oncology, Changsha Central Hospital, Changsha 410006, China
Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
Authors to whom correspondence should be addressed.
Academic Editor: Huang-Tsung Chang
Received: 18 November 2015 / Revised: 11 December 2015 / Accepted: 23 December 2015 / Published: 25 December 2015
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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. View Full-Text
Keywords: glycyrrhetinic acid; cytochrome P450 3A4; inhibitory effect; herb–drug interaction; IC50 glycyrrhetinic acid; cytochrome P450 3A4; inhibitory effect; herb–drug interaction; IC50

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MDPI and ACS Style

Lv, Q.-L.; Wang, G.-H.; Chen, S.-H.; Hu, L.; Zhang, X.; Ying, G.; Qin, C.-Z.; Zhou, H.-H. In Vitro and in Vivo Inhibitory Effects of Glycyrrhetinic Acid in Mice and Human Cytochrome P450 3A4. Int. J. Environ. Res. Public Health 2016, 13, 84.

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