Searching the cytochrome p450 enzymes for the metabolism of meranzin hydrate: a prospective antidepressant originating from Chaihu-Shugan-San

Xi Huang; Ying Guo; Wei-Hua Huang; Wei Zhang; Zhi-Rong Tan; Jing-Bo Peng; Yi-Cheng Wang; Dong-Li Hu; Dong-Sheng Ouyang; Jian Xiao; Yang Wang; Min Luo; Yao Chen

doi:10.1371/journal.pone.0113819

Searching the cytochrome p450 enzymes for the metabolism of meranzin hydrate: a prospective antidepressant originating from Chaihu-Shugan-San

PLoS One. 2014 Nov 26;9(11):e113819. doi: 10.1371/journal.pone.0113819. eCollection 2014.

Authors

Xi Huang¹, Ying Guo², Wei-Hua Huang², Wei Zhang², Zhi-Rong Tan², Jing-Bo Peng², Yi-Cheng Wang², Dong-Li Hu², Dong-Sheng Ouyang², Jian Xiao³, Yang Wang³, Min Luo³, Yao Chen¹

Affiliations

¹ Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, Hunan 410078, China; Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, 110 Xiangya road, Changsha, Hunan 410078, China; Laboratory of Ethnopharmacology, Institute of Integrated Traditional Chinese and Western Medicine, Xiangya Hospital, Central South University, 87 Xiangya Road, 410008 Changsha, China.
² Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, Hunan 410078, China; Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, 110 Xiangya road, Changsha, Hunan 410078, China.
³ Laboratory of Ethnopharmacology, Institute of Integrated Traditional Chinese and Western Medicine, Xiangya Hospital, Central South University, 87 Xiangya Road, 410008 Changsha, China.

Abstract

Meranzin hydrate (MH), an absorbed bioactive compound from the Traditional Chinese Medicine (TCM) Chaihu-Shugan-San (CSS), was first isolated in our laboratory and was found to possess anti-depression activity. However, the role of cytochrome P450s (CYPs) in the metabolism of MH was unclear. In this study, we screened the CYPs for the metabolism of MH in vitro by human liver microsomes (HLMs) or human recombinant CYPs. MH inhibited the enzyme activities of CYP1A2 and CYP2C19 in a concentration-dependent manner in the HLMs. The Km and Vmax values of MH were 10.3±1.3 µM and 99.1±3.3 nmol/mg protein/min, respectively, for the HLMs; 8.0±1.6 µM and 112.4±5.7 nmol/nmol P450/min, respectively, for CYP1A2; and 25.9±6.6 µM and 134.3±12.4 nmol/nmol P450/min, respectively, for CYP2C19. Other human CYP isoforms including CYP2A6, CYP2C9, CYP2D6, CYP2E1 and CYP3A4 showed minimal or no effect on MH metabolism. The results suggested that MH was simultaneously a substrate and an inhibitor of CYP1A2 and CYP2C9, and MH had the potential to perpetrate drug-drug interactions with other CYP1A2 and CYP2C19 substrates.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antidepressive Agents / metabolism*
Antidepressive Agents / pharmacology
Coumarins / metabolism*
Coumarins / pharmacology
Cytochrome P-450 CYP1A2 / metabolism
Cytochrome P-450 CYP2C19 / metabolism
Cytochrome P-450 CYP2D6 / metabolism
Cytochrome P-450 CYP2E1 / metabolism
Cytochrome P-450 Enzyme System / metabolism*
Enzyme Inhibitors / metabolism
Enzyme Inhibitors / pharmacology
Humans
Microsomes, Liver / drug effects
Microsomes, Liver / metabolism*
Plant Extracts / metabolism*
Plant Extracts / pharmacology

Substances

Antidepressive Agents
Coumarins
Enzyme Inhibitors
Plant Extracts
chaihu-shugan-san
meranzin hydrate
Cytochrome P-450 Enzyme System
Cytochrome P-450 CYP2E1
Cytochrome P-450 CYP1A2
Cytochrome P-450 CYP2C19
Cytochrome P-450 CYP2D6

Grants and funding

National Scientific Foundation of China (No. 81302850), General Financial Grant from the China Postdoctoral Science Foundation (No. 2013M531817 and 2014T70793), Science and Technology Plan Projects of Hunan Province (2014RS4011) to YC, General Financial Grant from the China Postdoctoral Science Foundation (No. 2013M542146) to JBP, 863 Project (No. 2012AA02A518) to WZ, Key Laboratory Funds of Hunan Province (13K003) and the Fundamental Research Funds for the Central South University (No. 1681–7608040003) to WHH. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.