Metabolism of menadione-6,7-3H

Taggart, William; Matschiner, John T.

doi:10.1021/bi00831a047

Cited by 58 publications

(30 citation statements)

References 17 publications

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“…In this case no K 2 species were found because warfarin blocks the conversion from K 1 to K 2 . [35][36][37] It is remarkable that, although K 1 was used (as measured by K 1 O) substantial tissue calcification was observed in this group (see Figure 2). After stopping the warfarin treatment, animals receiving the normal dose of K 1 showed vascular K 1 and K 2 levels that were in the range of control rats.…”

Section: Vitamin K Measurementsmentioning

confidence: 80%

Regression of warfarin-induced medial elastocalcinosis by high intake of vitamin K in rats

Schurgers

Spronk

Soute

et al. 2006

Blood

229

204

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Arterial calcification (AC) is generally regarded as an independent risk factor for cardiovascular morbidity and mortality. Matrix Gla protein (MGP) is a potent inhibitor of AC, and its activity depends on vitamin K (VK). In rats, inactivation of MGP by treatment with the vitamin K antagonist warfarin leads to rapid calcification of the arteries. Here, we investigated whether preformed AC can be regressed by a VK-rich diet. Rats received a calcification-inducing diet containing both VK and warfarin (W&K). During a second 6-week period, animals were randomly assigned to receive either W&K (3.0 mg/g and 1.5 mg/g, subsequently), a diet containing a normal (5 g/g) or high (100 g/g) amount of VK (either K 1 or K 2 ). Increased aortic calcium concentration was observed in the group that continued to receive W&K and also in the group changed to the normal dose of VK and AC progressed. Both the VK-rich diets decreased the arterial calcium content by some 50%. In addition, arterial distensibility was restored by the VK-rich diet. Using MGP antibodies, local VK deficiency was demonstrated at sites of calcification. This is the first study in rats demonstrating that AC and the resulting decreased arterial distensibility are reversible by high-VK intake. IntroductionArterial calcification is an important independent risk factor for the development of atherosclerosis, myocardial infarction, stroke, and renal disease. 1,2 Patients with manifest arterial calcification have an unfavorable prognosis compared with patients with no or mild calcification. 3,4 Therefore, the prevention or reversal of arterial calcification may lead to improved patient outcomes.For a long time it has been thought that calcification was a passive process and the end stage of cardiovascular disease. During the past 10 years, however, it has become clear that several osteoregulatory proteins, both stimulatory and inhibitory, are involved in the calcification of vascular tissue. [5][6][7][8] One of the strongest in vivo inhibitors of arterial calcification is matrix Gla protein (MGP). MGP was first discovered in bone, 9 but it is mainly produced by vascular smooth muscle cells and chondrocytes. Its function became clear in MGP-deficient mice, 10 which died within 6 to 8 weeks after birth as a result of rupture of the large arteries. Histochemical evaluation demonstrated complete calcification of the elastic fibers in the arterial vessels and a phenotypic change of smooth muscle cells into chondrocytes. MGP acts by direct inhibition of calcium crystal formation and regulates bone morphogenetic protein-2, a growth factor responsible for osteogenic differentiation. [11][12][13] Murshed et al 14 demonstrated that restoration of MGP exclusively in the vascular smooth muscle cells of the MGP-null mice completely rescued the vascular calcification phenotype. For this effect the MGP needed to be ␥-carboxylated because mutating the Gla residues into aspartic acid residues led to the synthesis of nonfunctional MGP and to the death of all animals.Vitamin K is an e...

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Section: Vitamin K Measurementsmentioning

confidence: 80%

Regression of warfarin-induced medial elastocalcinosis by high intake of vitamin K in rats

Schurgers

Spronk

Soute

et al. 2006

Blood

229

204

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“…Interestingly, warfarin has also been shown to block both the in vitro and in vivo conversion of menadione to menaquinone. 51,52 Taken together, this suggests that by inhibiting the conversion of endogenous menadione to menaquinone, anticoagulants could potentially leverage IDO inhibition by menadione while concomitantly interfering with the ability of menaquinone to support metastasis. Given the importance of both immune escape and metastasis in the pathophysiology of advanced cancers, further study in this area seems warranted.…”

Section: Discussionmentioning

confidence: 99%

Indoleamine 2,3-Dioxygenase Is the Anticancer Target for a Novel Series of Potent Naphthoquinone-Based Inhibitors

et al. 2008

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Indoleamine 2,3-dioxygenase (IDO) is emerging as an important new therapeutic target for the treatment of cancer, chronic viral infections, and other diseases characterized by pathological immune suppression. While small molecule inhibitors of IDO exist, there remains a dearth of high-potency compounds offering in vivo efficacy and clinical translational potential. In this study, we address this gap by defining a new class of naphthoquinone-based IDO inhibitors exemplified by the natural product menadione, which is shown in mouse tumor models to have similar antitumor activity to previously characterized IDO inhibitors. Genetic validation that IDO is the critical in vivo target is demonstrated using IDO-null mice. Elaboration of menadione to a pyranonaphthoquinone has yielded low nanomolar potency inhibitors, including new compounds which are the most potent reported to date (K i = 61-70 nM). Synthetic accessibility of this class will facilitate preclinical chemical-genetic studies as well as further optimization of pharmacological parameters for clinical translation.

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“…The generation of MK-4 from K 3 through the addition of a geranyl-geranyl side chain is well described (6,7) and is the probable source of the increased excretion of the 5C-and 7C-aglycones after K 3 supplementation. It may be possible to use this metabolite assay as an index of the tissue conversion of K 3 to MK-4.…”

Section: Discussionmentioning

confidence: 99%

“…Menadione (abbreviated K 3 ) is a synthetic vitamin K homolog that lacks the side chain at the 3 position and that, despite toxicity concerns and restricted biological activity, is still available in some countries as a pharmaceutical vitamin K preparation in the form of menadiol sodium phosphate (5) or similar water-soluble salt. The biological activity of K 3 in vivo depends entirely on its prenylation to MK-4 (6,7).…”

mentioning

confidence: 99%

Determination of the urinary aglycone metabolites of vitamin K by HPLC with redox-mode electrochemical detection

Harrington

Soper

Edwards

et al. 2005

Journal of Lipid Research

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We describe a method for the determination of the two major urinary metabolites of vitamin K as the methyl esters of their aglycone structures, 2-methyl-3-(3 -3 -carboxymethylpropyl)-1,4-naphthoquinone (5C-aglycone) and 2-methyl-3-(5 -carboxy-3 -methyl-2 -pentenyl)-1,4-naphthoquinone (7C-aglycone), by HPLC with electrochemical detection (ECD) in the redox mode. Urinary salts were removed by reversedphase (C 18 ) solid-phase extraction (SPE), and the predominantly conjugated vitamin K metabolites were hydrolyzed with methanolic HCl. The resulting carboxylic acid aglycones were quantitatively methylated with diazomethane and fractionated by normal-phase (silica) SPE. Final analysis was by reversed-phase (C 18 ) HPLC with a methanol-aqueous mobile phase. Metabolites were detected by amperometric, oxidative ECD of their quinol forms, which were generated by postcolumn coulometric reduction at an upstream electrode. The assay gave excellent linearity (typically, r 2 у 0.999) and high sensitivity with an on-column detection limit of Ͻ 3.5 fmol ( Ͻ 1 pg). The interassay precision was typically 10%. Metabolite recovery was compared with that of an internal standard [2-methyl-3-(7 -carboxy-heptyl)-1,4-naphthoquinone] added to urine samples just before analysis. Using this methodology, we confirmed that the 5C-and 7C-aglycones were major catabolites of both phylloquinone (vitamin K 1 ) and menaquinones (vitamin K 2 ) in humans. We propose that the measurement of urinary vitamin K metabolite excretion is a candidate noninvasive marker of total vitamin K status. -Harrington, D. J., R. Soper, C. Edwards, G. F. Savidge, S. J. Hodges, and M. J. Shearer. Determination of the urinary aglycone metabolites of vitamin K by HPLC with redox-mode electrochemical detection. J. Lipid Res.

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Metabolism of menadione-6,7-3H

Cited by 58 publications

References 17 publications

Regression of warfarin-induced medial elastocalcinosis by high intake of vitamin K in rats

Regression of warfarin-induced medial elastocalcinosis by high intake of vitamin K in rats

Indoleamine 2,3-Dioxygenase Is the Anticancer Target for a Novel Series of Potent Naphthoquinone-Based Inhibitors

Determination of the urinary aglycone metabolites of vitamin K by HPLC with redox-mode electrochemical detection

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