Menadione is a metabolite of oral vitamin K

Abstract

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.

Does the absence of ABCC6 (Multidrug Resistance Protein 6) in patients withPseudoxanthoma elasticumprevent the liver from providing sufficient vitamin K to the periphery?

“…1) was postulated to be an intermediate in this replacement. More recently Thijssen et al, 33 found that menadione-conjugates appear in the urine within 1 hour after an oral dose of K 1 or MK-4/7, showing that "the metabolic efficiency of side chain removal must be high". Where menadione is produced is still unclear, as some investigators 33 do not find any conversion of K 1 into MK-4 in cell lines, while others 34 find some conversion in brain.…”

“…More recently Thijssen et al, 33 found that menadione-conjugates appear in the urine within 1 hour after an oral dose of K 1 or MK-4/7, showing that "the metabolic efficiency of side chain removal must be high". Where menadione is produced is still unclear, as some investigators 33 do not find any conversion of K 1 into MK-4 in cell lines, while others 34 find some conversion in brain. The liver appears to be required for K 1 metabolism in the rat 35 and the possibility that the liver is a major menadione (or even MK-4) producer is not ruled out by the available data in our opinion.…”

“…Menadione itself cannot function as cofactor in K-dependent carboxylation, but many cells can take up menadione and convert it into MK-4, which does have cofactor activity. 33 What makes M-SG attractive as candidate substrate for ABCC6 is that Di Monte et al, 40 have shown already in 1984 that isolated rat hepatocytes convert menadione into M-SG and secrete this into the medium. This is not a minor reaction.…”

“…The liver appears to be required for K 1 metabolism in the rat 35 and the possibility that the liver is a major menadione (or even MK-4) producer is not ruled out by the available data in our opinion. In any case, menadione can be taken up and converted into MK-4 by various cell types 33 and tissues also readily take up MK-4. 31,34,36 Early work suggested that part of the liver K 1 and MK-4 is excreted into bile as polar metabolites, presumably K-conjugates.…”

“…31 If labelled menadione is used as substrate in the perfused rat liver, some of the polar metabolites in bile are menadione-glucuronides, 37 but later work showed that the main excretion product is glutathionyl-menadione. 38 Besides menadione-conjugates, 33 urine contains chain-shortened, glucuronide-conjugated K derivates. 31,39 The Hypothesis If PXE is due to a peripheral deficiency in K-dependent protein carboxylation, caused by the absence of a basolateral plasma membrane transporter, ABCC6, in the liver, it seems logical that ABCC6 must transport a factor into the circulation required for the carboxylation reaction.…”