Vitamin K

DATA No : VVK0005 INFORMANT : Tetsuya Nakamura

NAME : 1,4-Naphthalenedione, 2-methyl-3-(3,7,11,15-tetramethyl-2,6,10,14-hexadecatetraenyl)- / 1,4-Naphthoquinone, 2-methyl-3-(3,7,11,15-tetramethyl-2,6,10,14-hexadecatetraenyl)-

COMMON NAME	:	Menaquinone 4 / Vitamin K₂₍₂₀₎ / Vitamin MK4 / Menaquinone MK4 / Kaytwo / Menatetrenone.
SYMBOL	:	MK-4
FORMULA	:	C₃₁H₄₀O₂ MOL.WT (average) : 444.648

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BIOLOGICAL ACTIVITY

Menatetrenone at greater than 3 x 10 ^-⁶ M significantly inhibited the calcium release from mouse calvaria induced by 2 x 10 ^-¹⁰M of 1,25 (OH)₂D₃ or 10 ^-⁷M of prostaglandin E₂, and also inhibited osteoclast-like multinuleated cell formation induced by 10 ^-⁸M of 1,25(OH)₂D₃ in co-culture of spleen ells and stromal cells at the same concentrations. The inhibitory effect f menaterenone on the calcium release from calvaria was not affected by the addition of 3 x 10^-⁵M of warfarin an inhibtor of vitamin K cycle. (Ref. 0018)

PHYSICAL AND CHEMICAL PROPERTIES

MELTING POINT	:	35C(Ref. 0001)

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SPECTRAL DATA

UV SPECTRA	:	E¹^%₁_c_m (248mm) =438-440, in petroleum ether(Ref. 0001)

IR SPECTRA	:

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CHROMATOGRAM DATA

SOURCE

Rats were made vitamin K-deficiency by feeding them diet devoid of vitamin K. after one week, circulating prothrombin concentrations were between 5 and 10% of initial values and various amounts of phylloquinone, menaquinone-4, and menaquinone-9 were given in a single dose either subcutaneously, orally, or colorectally. The relative 'vitamin K acitivties' of these compounds were assessed by comparing their activity to support prothrombin synthesis after subcutaneous injection. The stimulation of prothormbin synthesis by menaquinone-9 lasted much longer than that by the two other K-vitamers, resulting in a substantially higher 'vitamin K activity' of menaquinone-9.(Ref. 0032)
[Table 0001] (Ref. 0032)

CHEMICAL SYNTHESIS

Condensation of 2-methyl-1,4-naphthohydroquinone (I) with geranyllinalool (II). I (27.5g) is dissolved in 65 ml of dry dioxane, 1.5 g of zinc chloride, and 3.5 ml of borontrifluoride etherate are added with stirring, and the mixture is heated to 50

. A solution of 0.87 mole of II per mole of I in 25 ml of dry dioxane is added, and the reaction mixture is stirred for 20 min longer. After cooling water and ether are added, the layers were separated and the etheral layer is washed. The ether solution is evaporated. The residue is dissolved in 200 ml of petroleum ether, the solution cooled to -50

. The precipitate centrifuged. The precipitate dissolved in 100 ml of ether, 20 g of dry silver oxide is added and the mixture shaken for 30 min.
After filtration the etheral solution is evaporated in vacuo, the residue dissolved in petroleum ether and chramatogphed. (Ref. 0017)

METABOLISM

Four metabolites of menaquinone-4 (MQ-4) were isolated from rat urine, bile and liver, and identified. On the basis of their structures, the metabolic pathways of MQ-4 are proposed as shown in
[Table 0002]. This pathway begins with w-methyl oxidation of the side chain followed by b-oxidation of the resultant MQ-4-COOH to K acid 1 and K acid 2. In the presence of warfarin, 2,3-epoxy-phylloquinone. This suggests that 2,3-epoxy-MQ-4 is converted to MQ-4 in the normal rat and that the reaction is inhibited by warfarin.(Ref. 0003)

GENETIC INFORMATION

NOTE

REFERENCES

[0001]

AUTHOR	:	Anonym. (1989) Vitamin K₁ in The Merck Index , 11th edition (Budavari, S., O'Neil, M. J., Smith, A., and Heckelman, P.E., eds), pp1580, Merck & Co., Inc., Rahway, N. J.
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VOL	:	PAGE : - ()

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[0003]

AUTHOR	:	Tadano, K., Yuzuriha, T., Sato, T., Fujita, T., Shimada, K., Hashimoto, K., and Satoh, T.
TITLE	:	Identification of menaquinone-4 metabolites in the rat PubMed ID:2630633
JOURNAL	:	J Pharmacobiodyn.
VOL	:	12 PAGE : 640-645 (1989)

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[0017]

AUTHOR	:	Mayer,H., and Isler,O.
TITLE	:	Synthesis of vitamin K.
JOURNAL	:	Methods in Enzymology
VOL	:	18 PAGE : 491 -547 (1971)

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[0018]

AUTHOR	:	Hara, K., Akiyama, Y., Nakamura, T., Murota, S., and Morita, I.
TITLE	:	The inhibitory effect of vitamin K2 (menatetrenone) on bone resorption may be related to its side chain PubMed ID:7756045
JOURNAL	:	Bone.
VOL	:	16 PAGE : 179-184 (1995)

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[0032]

AUTHOR	:	Groenen-van Dooren, M. M., Ronden, J. E., Soute, B. A., and Vermeer, C.
TITLE	:	Bioavailability of phylloquinone and menaquinones after oral and colorectal administration in vitamin K-deficient rats PubMed ID:7575640
JOURNAL	:	Biochem Pharmacol.
VOL	:	50 PAGE : 797-801 (1995)

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