In vitro effects of the citrus flavonoids diosmin, naringenin and naringin on the hepatic drug-metabolizing CYP3A enzyme in human, pig, mouse and fish

Viktoriia Burkina; Vladimir Zlabek; Ruth Halsne; Erik Ropstad; Galia Zamaratskaia

doi:10.1016/j.bcp.2016.04.011

In vitro effects of the citrus flavonoids diosmin, naringenin and naringin on the hepatic drug-metabolizing CYP3A enzyme in human, pig, mouse and fish

Biochem Pharmacol. 2016 Jun 15:110-111:109-16. doi: 10.1016/j.bcp.2016.04.011. Epub 2016 Apr 20.

Authors

Viktoriia Burkina¹, Vladimir Zlabek², Ruth Halsne³, Erik Ropstad⁴, Galia Zamaratskaia⁵

Affiliations

¹ University of South Bohemia in Ceske Budejovice, Faculty of Fisheries and Protection of Waters, South Bohemian Research Center of Aquaculture and Biodiversity of Hydrocenoses, Zatisi 728/II, 389 25 Vodnany, Czech Republic. Electronic address: vburkina@frov.jcu.cz.
² University of South Bohemia in Ceske Budejovice, Faculty of Fisheries and Protection of Waters, South Bohemian Research Center of Aquaculture and Biodiversity of Hydrocenoses, Zatisi 728/II, 389 25 Vodnany, Czech Republic. Electronic address: vzlabek@frov.jcu.cz.
³ Norwegian University of Life Sciences, Faculty of Veterinary Medicine and Biosciences, Department of Production Animal Clinical Sciences, P.O. 8146 Dep., N-0033 Oslo, Norway. Electronic address: ruth.halsne@nmbu.no.
⁴ Norwegian University of Life Sciences, Faculty of Veterinary Medicine and Biosciences, Department of Production Animal Clinical Sciences, P.O. 8146 Dep., N-0033 Oslo, Norway. Electronic address: erik.ropstad@nmbu.no.
⁵ University of South Bohemia in Ceske Budejovice, Faculty of Fisheries and Protection of Waters, South Bohemian Research Center of Aquaculture and Biodiversity of Hydrocenoses, Zatisi 728/II, 389 25 Vodnany, Czech Republic; Swedish University of Agricultural Sciences, Uppsala BioCenter, Department of Food Science, P.O. Box 7051, SE-750 07 Uppsala, Sweden. Electronic address: Galia.Zamaratskaia@slu.se.

PMID: 27107807
DOI: 10.1016/j.bcp.2016.04.011

Abstract

Flavonoids are known to have effects on cytochrome P450 enzymatic activity. However, little effort has been made to examine species differences and the relevance of studies on mammalian and fish microsomes so that extrapolations can be made to humans. Therefore, the effects of several naturally occurring flavonoids on the activity of CYP3A-dependent 7-benzyloxy-4-trifluoromethylcoumarin O-debenzylase (BFCOD) were evaluated in human, pig, mouse, and juvenile rainbow trout sources of hepatic microsomes. Each was exposed to three concentrations (1, 10, and 100μM) of diosmin, naringin, and naringenin. Naringenin competitively inhibited BFCOD activity (Ki values were 24.6μM in human, 15.6μM in pig, and 19.6μM in mouse microsomes). In fish, BFCOD activity was inhibited in a noncompetitive manner (Ki=7μM). Neither diosmin nor naringenin affected BFCOD activity in hepatic microsomes from the studied model organisms. These results suggest that dietary flavonoids potentially inhibit the metabolism of clinical drugs.

Keywords: CYP3A; Diosmin; Diosmin (PubChem CID: 5353588); Inhibition; Naringenin; Naringenin (PubChem CID: 932); Naringin; Naringin (PubChem CID: 25075).

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Citrus / chemistry
Coumarins / metabolism
Cytochrome P-450 CYP3A / genetics
Cytochrome P-450 CYP3A / metabolism*
Diosmin / pharmacology*
Enzyme Inhibitors / pharmacology*
Female
Flavanones / pharmacology*
Gene Expression
Humans
Hydrolysis
Kinetics
Liver / drug effects
Liver / enzymology
Male
Mice
Mice, Inbred ICR
Microsomes, Liver / drug effects*
Microsomes, Liver / enzymology
Oncorhynchus mykiss
Species Specificity
Swine

Substances

7-benzyloxy-4-trifluoromethylcoumarin
Coumarins
Enzyme Inhibitors
Flavanones
Diosmin
Cytochrome P-450 CYP3A
naringenin
naringin