Modeling the effect of phase II conjugations on topoisomerase I poisoning: pilot study with luteolin and quercetin

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Luca Dellafiora1, Pedro Mena, Daniele Del Rio

  • 1Molecular Modeling Laboratory, Department of Food Science, ‡The Laboratory of Phytochemicals in Physiology, Human Nutrition Unit, Department of Food Science, and §LS9 Bioactives and Health, Interlaboratory Group, Department of Food Science, University of Parma , 43125 Parma, Italy.

Journal of Agricultural and Food Chemistry
|May 30, 2014
PubMed

Insights

Flavonoid metabolites, like quercetin-3-O-glucuronide, may impact cancer chemotherapy by affecting human Topoisomerase I. This study computationally models how metabolism influences these topoisomerase poisons.

Area of Science:

  • Biochemistry
  • Pharmacology
  • Computational Chemistry

Background:

  • Topoisomerases are crucial enzymes in cell viability and targets for cancer chemotherapy.
  • Flavonoids and their glycosides are dietary compounds with potential health benefits, including topoisomerase poisoning.
  • Previous research overlooked the metabolic transformations of flavonoids after ingestion, which are critical for their biological activity.

Purpose of the Study:

  • To computationally model the impact of hepatic phase II conjugative metabolism on the topoisomerase poisoning activity of dietary flavonoids.
  • To identify potential flavonoid metabolites that could be prioritized for further experimental characterization.

Main Methods:

  • Development of an in silico computational procedure.
  • Modeling of glucuronidation and sulphation, key hepatic phase II metabolic reactions.
  • Focus on ubiquitous dietary flavonoids luteolin and quercetin.

Main Results:

  • Glucuronidation of flavonoids may enhance topoisomerase poisoning activity.
  • Sulphation of flavonoids may quench topoisomerase poisoning activity.
  • Quercetin-3-O-glucuronide emerged as a particularly promising metabolite for further investigation.

Conclusions:

  • Metabolic modifications significantly alter the topoisomerase poisoning potential of dietary flavonoids.
  • In silico approaches are valuable for prioritizing flavonoid metabolites for drug development and cancer research.
  • Quercetin-3-O-glucuronide warrants further experimental validation for its role in topoisomerase inhibition.

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