Inhibition effects of Vernonia cinerea active compounds against cytochrome P450 2A6 and human monoamine oxidases, possible targets for reduction of tobacco dependence

Drug Metab Pharmacokinet. 2015 Apr;30(2):174-81. doi: 10.1016/j.dmpk.2014.12.005. Epub 2015 Jan 2.


The human cytochrome P450 2A6 (CYP2A6) and monoamine oxidases (MAO-A and MAO-B), catalyzing nicotine and dopamine metabolisms, respectively, are two therapeutic targets of nicotine dependence. Vernonia cinerea, a medicinal plant commonly used for treatment of diseases such as asthma and bronchitis, has been shown reducing tobacco dependence effect among tobacco users. In the present study, we found eight active compounds isolated from V. cinerea that comprise inhibitory activity toward CYP2A6 and MAO-A and MAO-B enzymes using activity-guided assays, with coumarin as substrate of CYP2A6 and kynuramine of MAOs. These compounds were three flavones (apigenin, chrysoeriol, luteolin), one flavonol (quercetin), and four hirsutinolide-type sesquiterpene lactones (8α-(2-methylacryloyloxy)-hirsutinolide-13-O-acetate, 8α-(4-hydroxymethacryloyloxy)-hirsutinolide-13-O-acetate, 8α-tigloyloxyhirsutinolide-13-O-acetate, and 8α-(4-hydroxytigloyloxy)-hirsutinolide-13-O-acetate). Modes and kinetics of inhibition against the three enzymes were determined. Flavonoids possessed strong inhibitory effect on CYP2A6 in reversible mode, while inhibition by hirsutinolides was mechanism-based (NADPH-, concentration-, and time-dependence) and irreversible. Inhibition by hirsutinolides could not be reversed by dialysis and by addition of trapping agents or potassium ferricyanide. Flavonoids inhibited MAOs with variable degrees and were more prominent in inhibition toward MAO-A than hirsutinolides, while two of hirsutinolides inhibited MAO-B approximately comparable to two flavonoids. These results could have implications in combination of drug therapy for smoking cessation.

Keywords: Flavonoids; Hirsutinolides; MAO; P450 2A6; Vernonia cinerea.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Coumarins / metabolism
  • Cytochrome P-450 CYP2A6 / antagonists & inhibitors*
  • Cytochrome P-450 CYP2A6 / metabolism
  • Cytochrome P-450 Enzyme Inhibitors / chemistry
  • Cytochrome P-450 Enzyme Inhibitors / isolation & purification
  • Cytochrome P-450 Enzyme Inhibitors / pharmacology*
  • Drug Therapy, Combination
  • Humans
  • Kinetics
  • Kynuramine / metabolism
  • Models, Biological
  • Molecular Structure
  • Monoamine Oxidase / metabolism*
  • Monoamine Oxidase Inhibitors / chemistry
  • Monoamine Oxidase Inhibitors / isolation & purification
  • Monoamine Oxidase Inhibitors / pharmacology*
  • Phytotherapy
  • Plant Components, Aerial
  • Plant Extracts / chemistry
  • Plant Extracts / isolation & purification
  • Plant Extracts / pharmacology*
  • Plants, Medicinal
  • Recombinant Proteins / metabolism
  • Tobacco Use Disorder / drug therapy*
  • Tobacco Use Disorder / enzymology
  • Vernonia* / chemistry


  • Coumarins
  • Cytochrome P-450 Enzyme Inhibitors
  • Monoamine Oxidase Inhibitors
  • Plant Extracts
  • Recombinant Proteins
  • Kynuramine
  • coumarin
  • CYP2A6 protein, human
  • Cytochrome P-450 CYP2A6
  • Monoamine Oxidase
  • monoamine oxidase A, human