The effect of oxidation on berberine-mediated CYP1 inhibition: Oxidation behavior and metabolite-mediated inhibition

Sheng Nan Lo, Chien Chang Shen, Chia Yu Chang, Keng Chang Tsai, Chiung Chiao Huang, Tian Shung Wu, Yune Fang Ueng

Research output: Contribution to journalArticlepeer-review

9 Citations (Scopus)


The protoberberine alkaloid berberine carries methylenedioxy moiety and exerts a variety of pharmacological effects, such as antiinflammation and lipid-lowering effects. Berberine causes potent CYP1B1 inhibition, whereas CYP1A2 shows resistance to the inhibition. To reveal the influence of oxidative metabolism on CYP1 inhibition by berberine, berberine oxidation and the metabolitemediated inhibition were determined. After NADPH-fortified preincubation of berberine with P450, the inhibition of CYP1A1 and CYP1B1 variants (CYP1B1.1, CYP1B1.3, and CYP1B1.4) by berberine was not enhanced, and CYP1A2 remained resistant. Demethyleneberberine was identified as the most abundant metabolite of CYP1A1- and CYP1B1-catalyzed oxidations, and thalifendine was generated at a relatively low rate. CYP1A1-catalyzed berberine oxidation had the highest maximal velocity (Vmax) and exhibited positive cooperativity, suggesting the assistance of substrate binding when the first substrate was present. In contrast, the demethylenation by CYP1B1 showed the property of substrate inhibition. CYP1B1- catalyzed berberine oxidation had low Km values, but it had Vmax values less than 8% of those of CYP1A1. The dissociation constants generated from the binding spectrum and fluorescence quenching suggested that the low Km values of CYP1B1-catalyzed oxidation might include more than the rate constants describing berberine binding. The natural protoberberine/berberine fmetabolites with methylenedioxy ring-opening (palmatine, jatrorrhizine, and demethyleneberberine) and the demethylation (thalifendine and berberrubine) caused weak CYP1 inhibition. These results demonstrated that berberine was not efficiently oxidized by CYP1B1, and metabolism-dependent irreversible inactivation was minimal. Metabolites of berberine caused a relatively weak inhibition of CYP1.

Original languageEnglish
Pages (from-to)1100-1107
Number of pages8
JournalDrug Metabolism and Disposition
Issue number7
Publication statusPublished - 2015 Jul 1

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Pharmaceutical Science


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