Louvet Marie-Sophie, Gault Gilbert, Lefebvre Sébastien, Popowycz Florence, Boulven Manon, Besse Stéphane, Benoit Etienne, Lattard Virginie, Grancher Denis
USC 1233 INRA-Vetagro Sup, Veterinary School of Lyon, 1 avenue Bourgelat, 69280 Marcy l'Etoile, France.
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.
Phytochemistry. 2015 Oct;118:124-30. doi: 10.1016/j.phytochem.2015.08.012. Epub 2015 Aug 24.
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.
已描述了两种可区分的阿魏（Ferula communis）化学型：“无毒”化学型，其主要成分是胡萝卜烷酯；以及“有毒”化学型，含有异戊烯基化香豆素，如阿魏醇和阿魏素。阿魏醇和阿魏素是4-氧化分子，如双香豆素和华法林，是最早开发的抗维生素K分子。抗维生素K分子特异性抑制VKORC1，这是一种维生素K循环所必需的酶。后者参与凝血因子II、VII、IX、X的激活。阿魏醇对VKORC1的抑制作用在大鼠中得到证实，但对于暴露于阿魏的其他物种则未得到证实，而体内研究表明动物对阿魏醇的易感性存在差异。阿魏素对VKORC1的抑制作用从未得到证实。本研究的目的是比较这两种化合物对暴露于阿魏的不同物种的VKORC1的抑制作用。从肝脏微粒体评估了每个物种的维生素K环氧化物活性，并对阿魏醇和阿魏素的抑制作用进行了表征。结果表明，阿魏醇和阿魏素能够抑制所有分析物种的VKORC1。然而，不同物种对阿魏醇和阿魏素的易感性存在差异，这表明对阿魏“有毒”化学型的易感性不同。
