title: Comparative inhibitory effect of prenylated coumarins, ferulenol and ferprenin, contained in the 'poisonous chemotype' of Ferula communis on mammal liver microsomal VKORC1 activity.
abstract: Two distinguishable chemotypes of Ferula communis have been described: the 'nonpoisonous' chemotype, containing as main constituents the daucane esters; and the 'poisonous' chemotype containing prenylated coumarins, such as ferulenol and ferprenin. Ferulenol and ferprenin are 4-oxygenated molecules such as dicoumarol and warfarin, the first developed antivitamin K molecules. Antivitamin K molecules specifically inhibit VKORC1, an enzyme essential for recycling vitamin K. This latest is involved in the activation of clotting factors II, VII, IX, X. The inhibiting effect of ferulenol on VKORC1 was shown in rat, but not for species exposed to F. communis while in vivo studies suggest differences between animal susceptibility to ferulenol. The inhibiting effect of ferprenin on VKORC1 was never demonstrated. The aim of this study was to compare the inhibiting effect of both compounds on VKORC1 of different species exposed to F. communis. Vitamin K epoxide activity was evaluated for each species from liver microsomes and inhibiting effect of ferulenol and ferprenin was characterized. Ferulenol and ferprenin were shown to be able to inhibit VKORC1 from all analyzed species. Nevertheless, susceptibility to ferulenol and ferprenin presented differences between species, suggesting a different susceptibility to 'poisonous' chemotypes of F. communis.
authors: USC 1233 INRA-Vetagro Sup, Veterinary School of Lyon, 1 avenue Bourgelat, 69280 Marcy l'Etoile, France.
authors: Marie-Sophie
authors: MS
authors: Louvet
authors: USC 1233 INRA-Vetagro Sup, Veterinary School of Lyon, 1 avenue Bourgelat, 69280 Marcy l'Etoile, France.
authors: Gilbert
authors: G
authors: Gault
authors: USC 1233 INRA-Vetagro Sup, Veterinary School of Lyon, 1 avenue Bourgelat, 69280 Marcy l'Etoile, France.
authors: Sébastien
authors: S
authors: Lefebvre
authors: Laboratoire de Chimie Organique et Bio-organique, Institut National des Sciences Appliquées (INSA-Lyon), ICBMS-CNRS-UMR 5246, 20 Avenue Albert Einstein, F-69621 Villeurbanne Cedex, France.
authors: Florence
authors: F
authors: Popowycz
authors: Laboratoire de Chimie Organique et Bio-organique, Institut National des Sciences Appliquées (INSA-Lyon), ICBMS-CNRS-UMR 5246, 20 Avenue Albert Einstein, F-69621 Villeurbanne Cedex, France.
authors: Manon
authors: M
authors: Boulven
authors: USC 1233 INRA-Vetagro Sup, Veterinary School of Lyon, 1 avenue Bourgelat, 69280 Marcy l'Etoile, France.
authors: Stéphane
authors: S
authors: Besse
authors: USC 1233 INRA-Vetagro Sup, Veterinary School of Lyon, 1 avenue Bourgelat, 69280 Marcy l'Etoile, France.
authors: Etienne
authors: E
authors: Benoit
authors: USC 1233 INRA-Vetagro Sup, Veterinary School of Lyon, 1 avenue Bourgelat, 69280 Marcy l'Etoile, France. Electronic address: virginie.lattard@vetagro-sup.fr.
authors: Virginie
authors: V
authors: Lattard
authors: USC 1233 INRA-Vetagro Sup, Veterinary School of Lyon, 1 avenue Bourgelat, 69280 Marcy l'Etoile, France.
authors: Denis
authors: D
authors: Grancher
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D003374:Coumarins / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D005309:Ferula / Q000737:chemistry*; D005602:France; D006041:Goats; D006736:Horses; D008099:Liver / Q000378:metabolism*; D008862:Microsomes, Liver / Q000187:drug effects*; D008969:Molecular Sequence Data; D054876:Prenylation; D051381:Rats; D013552:Swine; D010837:Vitamin K 1 / Q000494:pharmacology; D064417:Vitamin K Epoxide Reductases / Q000187:drug effects*; D014859:Warfarin / Q000737:chemistry
chemical_list: D003374:Coumarins; C000608061:ferprenin; D014859:Warfarin; C092340:ferulenol; D010837:Vitamin K 1; C578519:VKORC1 protein, rat; D064417:Vitamin K Epoxide Reductases
keywords: Ferprenin; Ferula communis L. (Apiaceae); Ferulenol; Inhibition constant; Interspecies variability; VKORC1