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) mg/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 -2 h and peaked at about 3 h after intake. Amounts of menadione excreted in 24 h 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 0 ,3 0 -dihydrophylloquinone administered orally. In archived samples from a depletion/repletion study (Booth et al. (2001) Am J Clin Nutr 74, 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.

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The presence of even one copy of CYP2C9*3 reduces profoundly the metabolic clearance of S -acenocoumarol. As a result the first-pass effect of elimination is abolished and the maintenance time is increased. S -Acenocoumarol, which is normally clinically inactive, will now exert main anticoagulant activity.

Paracetamol (acetaminophen) is generally considered to be the analgesic of choice for patients undergoing oral anticoagulant therapy. Occasionally, however, interactions have been reported with therapeutic doses of the analgesic, e.g. if the drug is taken for a longer period of time. The mechanism of this interaction is not clearly understood. We investigated the effects of paracetamol and its toxic metabolite N-acetyl-para-benzoquinoneimine (NAPQI) on in vitro vitamin K-dependent gamma-carboxylase (VKD-carb) and vitamin K epoxide reductase (VKOR) activities. Paracetamol had no effect in either enzymatic reactions. NAPQI, on the other hand, appeared to interfere with VKD carb activity via two mechanisms; 1) oxidation of the cofactor vitamin K-hydroquinone, 2) inactivation of the enzyme. The inactivation, in micromolar ranges, is not reversible and may be the result of covalent binding of NAPQI with functional amino acids. NAPQI also inhibited VKOR, but at higher concentrations. Unexpectedly, N-acetylcysteine was found to inhibit VKOR activity at concentrations that are obtained during rescue therapy of paracetamol intoxication. We conclude that, the potentiation of the oral anticoagulant effect by paracetamol is likely to result from NAPQI-induced inhibition of enzymes of the vitamin K cycle, particularly VKD-carb.

As one of the important dietary antioxidants, (-)-epicatechin is a potent reactive oxygen species (ROS) scavenger involved in the redox modulation of the cell. When scavenging ROS, (-)-epicatechin will donate two electrons and become (-)-epicatechin quinone, and thus take over part of the oxidative potential of the ROS. The aim of the study is to determine where this chemical reactivity resides in (-)-epicatechin quinone. When this reactivity is spread out over the entire molecule, i.e. over the AC-ring and B-ring, this will lead to partial epimerization of (-)-epicatechin quinone to (-)-catechin quinone. In our experiments, (-)-epicatechin quinone was generated with tyrosinase. The formation of (-)-epicatechin quinone was confirmed by trapping with GSH, and identification of (-)-epicatechin-GSH adducts. Moreover, (-)-epicatechin quinone could be detected using Q-TOF/MS despite its short half-life. To detect the epimerization, the ability of ascorbate to reduce the unstable flavonoid quinones into the corresponding stable flavonoids was used. The results showed that the reduction of the formed (-)-epicatechin quinone by ascorbate did not result in the formation of an appreciable amount of (-)-catechin. Therefore it can be concluded that the chemical reactivity of (-)-epicatechin quinone mainly resides in its B-ring. This could be corroborated by quantum chemical calculations. Understanding the stabilization of the (-)-epicatechin quinone will help to differentiate between flavonoids and to select the appropriate compound for a specific disorder.