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Menadione is a metabolite of oral vitamin K

Published online by Cambridge University Press:  08 March 2007

Henk H. W. Thijssen*
Department of Pharmacology, Cardiovascular Research Institute Maastricht, University of MaastrichtPO Box 616, 6200 MD Maastricht, The Netherlands
Lily M. T. Vervoort
Department of Pharmacology, Cardiovascular Research Institute Maastricht, University of MaastrichtPO Box 616, 6200 MD Maastricht, The Netherlands
Leon J. Schurgers
Department of Biochemistry, University of Maastricht, The Netherlands
Martin J. Shearer
The Centre for Haemostasis and Thrombosis, St. Thomas's Hospital, London, UK
*Corresponding author: Dr Henk H. W. Thijssen, fax +31 43 3884149, email
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Phylloquinone is converted into menaquinone-4 and accumulates in extrahepatic tissues. Neither the route nor the function of the conversion is known. One possible metabolic route might be the release of menadione from phylloquinone by catabolic activity. In the present study we explored the presence of menadione in urine and the effect of vitamin K intake on its excretion. Menadione in urine was analysed by HPLC assay with fluorescence detection. Urine from healthy male volunteers was collected before and after administration of a single dose of K vitamins. Basal menadione excretion in non-supplemented subjects (n 6) was 5·4 (sd 3·2) μg/d. Urinary menadione excretion increased greatly after oral intake of the K vitamins, phylloquinone and menaquinone-4 and -7. This effect was apparent within 1–2h and peaked at about 3h after intake. Amounts of menadione excreted in 24h after vitamin K intake ranged, on a molar basis, from 1 to 5% of the administered dose, indicating that about 5–25% of the ingested K vitamins had been catabolized to menadione. Menadione excretion was not enhanced by phylloquinone administered subcutaneously or by 2′,3′-dihydrophylloquinone administered orally. In archived samples from a depletion/repletion study (Booth et al. (2001)Am J Clin Nutr74, 783–790), urinary menadione excretion mirrored dietary phylloquinone intake. The present study shows that menadione is a catabolic product of K vitamins formed after oral intake. The rapid appearance in urine after oral but not subcutaneous administration suggests that catabolism occurs during intestinal absorption. The observations make it likely that part of the menaquinone-4 in tissues results from uptake and prenylation of circulating menadione

Research Article
Copyright © The Nutrition Society 2006


Berkner, KL & Runge, KWThe physiology of vitamin K nutriture and vitamin K-dependent protein function in atherosclerosis. J Thromb Haemost 2005 2 21182132CrossRefGoogle Scholar
Billeter, MBollinger, W&Martius, CUntersuchungen über die Umwandlung von verfütterten K-vitaminen durch austauch der Seitenkette und die rolle der Darmbakterien hierbei. Biochem Z 1964 340 290303Google Scholar
Billeter, M&Martius, CÜ ber die Umwandlung von Phyllochinon (Vitamin K1) in Vitamin K2(20) in Tierkörper. Biochem Z 1960 333 430439Google Scholar
Booth, SLLichtenstein, AHAH,, M, McKeown, NMWood, RJSaltzman, E & Gundberg, CMEffects of a hydrogenated form of vitamin K on bone formation and resorption Am J Clin Nutr 2001 74 783790CrossRefGoogle ScholarPubMed
Carrie, IPortoukalian, JVicaretti, RRochford, JPotvin, S &Ferland, GMenaquinone-4 concentration is correlated with sphingolipid concentrations in rat brain. J Nutr 2004 134 167172CrossRefGoogle ScholarPubMed
Conley, JM&Stein, KThe production of menaquinones (vitamin K2) by intestinal bacteria and their role in maintaining coagulation homeostasis. Prog Food Nutr Sci 1992 16 307343Google Scholar
Davidson, RTFoley, ALEngelke, JA &Suttie, JWConversion of dietary phylloquinone to tissue menaquinone-4 in rats is not dependent on gut bacteria. J Nutr 1998 128 220223CrossRefGoogle Scholar
Hagstrom, JNBovill, EGSoll, RFDavidson, KW&Sadowski, JAThe pharmacokintics and lipoprotein fraction distribution of intramuscular vs. oral vitaminK1 supplementation in women of childbearing age: effects on hemostasis. Thromb Haemost 1995 74 14861490Google Scholar
Haroon, YBacon, DS&Sadowski, JAChemical reduction system for the detection of phylloquinone (vitamin K1) and menaquinones (vitamin K2) J Chromatogr 1987 384 383389CrossRefGoogle ScholarPubMed
Harrington, DJSoper, REdwards, CSavidge, GFHodges, SJ&Shearer, MJDetermination of the urinary aglycone metabolites of vitamin K by HPLC with redox-mode electrochemical detection. J Lipid Res 2005 46 10531060CrossRefGoogle ScholarPubMed
Hu, OY-PWu, C-YChan, W-K & Wu, FY-HDetermination of anticancer drug vitamin K3 in plasma by high-performance liquid chromatography J Chromatogr 1995 666 299305Google ScholarPubMed
Imada, IWatanabe, MMatsumoto, N&Morimoto, HMetabolism of ubiquinone-7. Biochemistry 1970 9 28702878CrossRefGoogle ScholarPubMed
Kohlmeier, MSalomon, ASaupe, J&Shearer, MJTransport of vitamin K to bone in humans J Nutr 1996 126Suppl. 1192S1196SCrossRefGoogle ScholarPubMed
Lamon-Fava, SSadowski, JA, Davidson, KWO'Brien, MEMcNamara, JR&Schaefer, EJPlasma lipoproteins as carriers of phylloquinone (vitamin K1) in humans. Am J Clin Nutr 1998 67 12261231CrossRefGoogle ScholarPubMed
Losito, ROwen, CA&Flock, EVMetabolism of [14C]menadione. Biochemistry 1998 6 6268CrossRefGoogle Scholar
Resh, MDMembrane targeting of lipid modified signal transduction proteins. Subcell Biochem 2004 37 217232CrossRefGoogle ScholarPubMed
Ronden, JEDrittij-Reijnders, MJVermeer, C&Thijssen, HHWIntestinal flora is not an intermediate in the phylloquinone–menaquinone-4 conversion in the rat Biochim Biophys Acta 1998 1379 6975CrossRefGoogle Scholar
Roskoski, RProtein prenylation: a pivotal posttranslationaln process. Biochem Biophys Res Commun 2003 303 17CrossRefGoogle ScholarPubMed
Sakamoto, NKimura, MHiraike, H&Itokawa, YChanges of phylloquinone and menaquinone-4 concentrations in rat live rafter oral, intravenous and intraperitoneal administration. Int J Vitam Nutr Res 1996 66 322328Google Scholar
Sato, TOzaki, RKamo, SHara, YKonishi, SIsobe, YSaitoh, S&Harada, HThe biological activity and tissue distribution of 2,3-dihydrophylloquinone in rats. Biochim Biophys Acta 2003 1622 145150CrossRefGoogle ScholarPubMed
Schurgers, LJ&Vermeer, CDetermination of phylloquinone and menaquinones in food. Effect of food matrix on circulating vitamin K concentrations Haemostasis 2000 30 298307Google ScholarPubMed
Schurgers, LJ&Vermeer, CDifferential lipoprotein transport pathways of K-vitamins in healthy subjects Biochim Biophys Acta 2002 1570 2732CrossRefGoogle ScholarPubMed
Shearer, MJVitamin, KLancet 1995 345 229234CrossRefGoogle Scholar
Shearer, MJRole of vitamin K and Gla proteins in the pathophysioloy of osteoporosis and vascular calcification Curr Opin Clin Nutr Metab Care 2000 3 433438CrossRefGoogle Scholar
Shearer, MJ, McBurney, A&Barkhan, PStudies on the absorption and metabolism of phylloquinone (vitamin K1) in man Vitam Horm 1974 32 513542CrossRefGoogle ScholarPubMed
Sundaram, KSFan, J-HEngelke, JAFoley, ALSuttie, JW&Lev, MVitamin K status influences brain sulfatide metabolism in young mice and rats J Nutr 1996 126 27462751Google ScholarPubMed
Taggart, WV&Matschiner, JTMetabolism of menadione-6, 7-3H in the rat. Biochemistry 1969 8 11411146CrossRefGoogle ScholarPubMed
Thijssen, HHW&Drittij-Reijnders, MJVitamin K distribution in rat tissues: dietary phylloquinone is a source of tissue menaquinone-4. Br J Nutr 1994 72 415425CrossRefGoogle ScholarPubMed
Thijssen, HHW&Drittij-Reijnders, MJVitamin K status in human tissues: tissue-specific accumulation of phylloquinone and menaquinone-4. Br J Nutr 1996 75 121127CrossRefGoogle ScholarPubMed
Thijssen, HHWDrittij-Reijnders, MJ&Fischer, MAJGPhylloquinonand and menaquinone-4 distribution in rats: synthesis rather than uptake determines menaquinone-4 organ concentrations. J Nutr 1996 126 537543CrossRefGoogle ScholarPubMed
Thijssen, HHWDrittij, MJVermeer, C&Schoffelen, EMenaquinone-4 in breast milk is derived from dietary phylloquinone. Br J Nutr 2002 87 219226CrossRefGoogle ScholarPubMed
Thomas, DDKrzykowski, KJEngelke, JA&Groblewski, GEExocrine pancreatic secretion of phospholipid, menaquinone-4, and caveolin-1 in vivo. Biochem Biophys Res Commun 2004 319 974979CrossRefGoogle ScholarPubMed
Usui, YNishimura, NKobayashi, NOkanone, TKimoto, M&Ozawa, KMeasurement of vitamin K in human liver by gradient elution high-performance liquid chromatography using platinumblack catalyst reduction and fluorometric detection. J Chromatogr 1989 489 291301CrossRefGoogle Scholar