In vitro metabolism of 4, 5-dimethoxycanthin-6-one by human liver microsomes and its inhibition on human CYP1A2

  • Life Sci. 2017 Dec 1;190:46-51. doi: 10.1016/j.lfs.2017.09.031.
Xiaolei Miao  1 ,  Jiaojiao You  1 ,  Junjun Wang  2 ,  Yong Chen  3
Affiliations
  • 1. Hubei Province Key Laboratory of Biotechnology of Chinese Traditional Medicine, Hubei Collaborative Innovation Center for Green Transformation of Bio-resources, Hubei University, Wuhan, Hubei 430062, China.
  • 2. Hubei Province Key Laboratory of Biotechnology of Chinese Traditional Medicine, Hubei Collaborative Innovation Center for Green Transformation of Bio-resources, Hubei University, Wuhan, Hubei 430062, China. Electronic address: [email protected].
  • 3. Hubei Province Key Laboratory of Biotechnology of Chinese Traditional Medicine, Hubei Collaborative Innovation Center for Green Transformation of Bio-resources, Hubei University, Wuhan, Hubei 430062, China. Electronic address: [email protected].
PMID: 28962866 DOI: 10.1016/j.lfs.2017.09.031
Abstract

Aims: P. quassioides is a traditional Chinese medicine used for the treatment of gastroenteritis, snakebite, Infection and hypertension in China. 4, 5-dimethoxycanthin-6-one is one of the main active canthinone alkaloid isolated from P. quassioides. The aim of this work was to identify the cytochrome P (CYP) 450 Enzymes responsible for the metabolism of 4, 5-dimethoxycanthin-6-one (DCO) and to evaluate the inhibitory effect of DCO on CYP activity in human liver microsomes (HLM) in vitro.

Materials and methods: the CYP isoforms responsible for DCO metabolism and the inhibitory effects of DCO on CYP activity was studied in HLM.

Key findings: The in vitro metabolic enzyme of DCO was CYP3A4 (mediated the formation of metabolites M1-M5), CYP2C9 (mediated the formation of metabolites M1-M3, M6 and M8) and CYP2D6 (mediated the formation of metabolite M3) in HLM. Furthermore, the present work found that DCO uncompetitively inhibited CYP1A2-mediated phenacetin O-deethylation with an IC50 value of 1.7μM and a Ki value of 2.6μM.

Significance: The results suggested that the metabolic interaction should be existed when the substrate drugs of CYP1A2 were co-administered with DCO or traditional Chinese medicine containing it, such as the extract of P. quassioides and Kumu injection.

Keywords
4,5-dimethoxycanthin-6-one; Cytochrome P450; Human liver microsome; Metabolic interaction.
Products