Journal Article

Transformation of berberine to its demethylated metabolites by the CYP51 enzyme in the gut microbiota

Zhang, Zheng-Wei, Pan, Li-Bin, Jiang, Jian-Dong, Fu, Jie, Peng, Ran, Han, Pei, Ma, Shu-Rong, Yu, Hang, Cong, Lin, Wang, Yan

2021

Overview

Berberine (BBR) is an isoquinoline alkaloid extracted from Coptis chinensis that improves diabetes, hyperlipidemia and inflammation. Due to the low oral bioavailability of BBR, its mechanism of action is closely related to the gut microbiota. This study focused on the CYP51 enzyme of intestinal bacteria to elucidate a new mechanism of BBR transformation by demethylation in the gut microbiota through multiple analytical techniques. First, the docking of BBR and CYP51 was performed; then, the pharmacokinetics of BBR was determined in ICR mice in vivo, and the metabolism of BBR in the liver, kidney, gut microbiota and single bacterial strains was examined in vitro. Moreover, 16S rRNA analysis of ICR mouse feces indicated the relationship between BBR and the gut microbiota. Finally, recombinant E. coli containing cyp51 gene was constructed and the CYP51 enzyme lysate was induced to express. The metabolic characteristics of BBR were analyzed in the CYP51 enzyme lysate system. The results showed that CYP51 in the gut microbiota could bind stably with BBR, and the addition of voriconazole (a specific inhibitor of CYP51) slowed down the metabolism of BBR, which prevented the production of the demethylated metabolites thalifendine and berberrubine. This study demonstrated that CYP51 promoted the demethylation of BBR and enhanced its intestinal absorption, providing a new method for studying the metabolic transformation mechanism of isoquinoline alkaloids in vivo. [Display omitted] •The demethylation metabolism of natural drugs difficult to absorb through the gut microbiota was first reported.•Six different methods were presented to explain the metabolic mechanism of natural isoquinoline alkaloids.•The findings provided a new idea for studying the mechanism of drug metabolism of gut microbiota.

• Publisher: Elsevier B.V,Xi'an Jiaotong University, Journal of Pharmaceutical Analysis,State Key Laboratory of Bioactive Substance and Function of Natural Medicines,Institute of Materia Medica,Chinese Academy of Medical Sciences & Peking Union Medical College,Beijing,100050,China,Xi'an Jiaotong University,Elsevier
• Subject: Alkaloids / Berberine / Bioavailability / Biotechnology / Biotransformation / CYP51 / CYP51 gene / Demethylated metabolite / Demethylation / Diabetes mellitus / Digestive system / Disease / Enzymes / Gas flow / Gastrointestinal tract / Genetic transformation / Gut microbiota / Hyperlipidemia / Intestinal absorption / Intestinal microflora / Intestine / Kidneys / Laboratory animals / Medical research / Metabolism / Metabolites / Microbiota / Original / Pharmacokinetics / Proteins / rRNA 16S / Sterols / Voriconazole