Menatetrenone

MK-4 is the major form of Vitamin K in vertebrate animals, including humans and common forms of meat animals. It is produced via conversion of vitamin K₁ in the body, specifically in the testes, pancreas and arterial walls.{{cite journal | vauthors = Shearer MJ, Newman P | title = Metabolism and cell biology of vitamin K | journal = Thrombosis and Haemostasis | volume = 100 | issue = 4 | pages = 530–47 | date = October 2008 | pmid = 18841274 | doi = 10.1160/TH08-03-0147 | s2cid = 7743991 }} The conversion is not dependent on gut bacteria, occurring in germ-free rats{{cite journal | vauthors = Davidson RT, Foley AL, Engelke JA, Suttie JW | title = Conversion of dietary phylloquinone to tissue menaquinone-4 in rats is not dependent on gut bacteria | journal = The Journal of Nutrition | volume = 128 | issue = 2 | pages = 220–3 | date = February 1998 | pmid = 9446847 | doi = 10.1093/jn/128.2.220 | doi-access = free }}{{cite journal | vauthors = Ronden JE, Drittij-Reijnders MJ, Vermeer C, Thijssen HH | title = Intestinal flora is not an intermediate in the phylloquinone-menaquinone-4 conversion in the rat | journal = Biochimica et Biophysica Acta (BBA) - General Subjects | volume = 1379 | issue = 1 | pages = 69–75 | date = January 1998 | pmid = 9468334 | doi = 10.1016/S0304-4165(97)00089-5 }} and in parenterally-administered K₁ in rats.{{cite journal | vauthors = Thijssen HH, Drittij-Reijnders MJ | title = Vitamin K distribution in rat tissues: dietary phylloquinone is a source of tissue menaquinone-4 | journal = The British Journal of Nutrition | volume = 72 | issue = 3 | pages = 415–25 | date = September 1994 | pmid = 7947656 | doi = 10.1079/BJN19940043 | doi-access = free }}{{cite journal | vauthors = Will BH, Usui Y, Suttie JW | title = Comparative metabolism and requirement of vitamin K in chicks and rats | journal = The Journal of Nutrition | volume = 122 | issue = 12 | pages = 2354–60 | date = December 1992 | pmid = 1453219 | doi = 10.1093/jn/122.12.2354 | doi-access = free }} Tissues that accumulate high amounts of MK-4 have a capacity to convert up to 90% of the available K₁ into MK-4.{{dubious|reason=Shearer reports that the two article show high conversion of menadione but variable conversion of K1|date=July 2023}}

K₁ is converted to MK-4 in three steps:{{cite journal | vauthors = Shearer MJ, Newman P | title = Recent trends in the metabolism and cell biology of vitamin K with special reference to vitamin K cycling and MK-4 biosynthesis | journal = Journal of Lipid Research | volume = 55 | issue = 3 | pages = 345–362 | date = March 2014 | pmid = 24489112 | pmc = 3934721 | doi = 10.1194/jlr.R045559 |doi-access=free }}

• Removal of the phytyl tail to form menadione (K3; unknown enzyme);
• Reduction of menadione to menadiol (likely NQO1);
• Attachment of GGPP tail to form menaquinol-4, the reduced form of MK-4 (UBIAD1)

The second and third steps are known to happen in target tissue. The first step is proposed to happen mainly in the intestines.

Menatetrenone is approved in Japan for second-line treatment of postmenopausal osteoporosis. Evidence is restricted to small-scale RCTs; the minimum effective dose (for bone mass parameters) is 45 mg, much higher than the Daily Value for vitamin K (80 μg).{{cite journal | vauthors = Iwamoto J | title = Vitamin K₂ therapy for postmenopausal osteoporosis | journal = Nutrients | volume = 6 | issue = 5 | pages = 1971–80 | date = May 2014 | pmid = 24841104 | pmc = 4042573 | doi = 10.3390/nu6051971 | doi-access = free |quote=administered daily doses of 15, 45, 90, and 135 mg revealed that 45 mg was the minimum effective dose for improving bone mass parameters evaluated by microdensitometry and/or single photon absorptiometry in postmenopausal women with osteoporosis}}

420 μg of oral MK-4, in a single-dose or spread out over 7 days, does not cause detectable changes in serum MK-4 level in healthy women, whereas MK-7 produces the expected increases in MK-7 levels.{{cite journal | vauthors = Sato T, Schurgers LJ, Uenishi K | title = Comparison of menaquinone-4 and menaquinone-7 bioavailability in healthy women | journal = Nutrition Journal | volume = 11 | issue = 93 | pages = 93 | date = November 2012 | pmid = 23140417 | pmc = 3502319 | doi = 10.1186/1475-2891-11-93 | doi-access = free }}

The minimum effective oral dose to change serum osteocalcin levels is 1500 μg/d, where as oral MK-7 is effective on this parameter at 45 μg/d, a level more in line with nutritional intake. In addition, rat studies show that oral MK-7 is better at increasing extrahepatic tissue levels of MK-4 than oral MK-4.

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{{Spoken Wikipedia|MenatetrenoneA.ogg|date=2012-09-08}}

{{Drugs for treatment of bone diseases}}

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Category:1,4-Naphthoquinones

Category:Diterpenes

Category:Vitamin K