Vitamin K2 is a group name for a family of related compounds, generally
subdivided into short-chain menaquinones and the long-chain menaquinones, of
which MK-7, MK-8 and MK-9 are nutritionally the most recognized.
Forms All K vitamins are similar in structure:
they share a “quinone” ring, but differ in the length and degree of saturation
of the carbon tail and the number of “side chains”. The number of side chains
is indicated in the name of the particular menaquinone and this
influences the transport to different target tissues.
Mechanism of action The mechanism of action of vitamin K2 is
similar to vitamin K1. Traditionally, K vitamins were recognized as the factor
required for coagulation, but the functions performed by this vitamin
group were revealed to be much more complex. K vitamins play an essential
role as cofactor for the enzyme γ-glutamyl carboxylase, which is
involved in vitamin K-dependent carboxylation of the gla domain in "Gla
proteins" to γ-carboxy glutamic acid in these proteins).
Carboxylation of these vitamin K-dependent Gla-proteins, besides being
essential for the function of the protein, is also an important vitamin
recovery mechanism since it serves as a recycling pathway to recover vitamin K
from its epoxide metabolite for reuse in carboxylation.
Several human Gla-containing proteins synthesized in several different types
of tissues have been discovered: Coagulation factors, as well as
anticoagulation proteins. These Gla-proteins are synthesized in the
liver and play an important role in blood homeo-stasis.
Osteocalcin. This non-collagenous protein is secreted by osteoblasts and
plays an essential role in the formation of mineral in bone.
Matrix gla protein. This calcification inhibitory protein is found in numerous
body tissues, but its role is most pronounced in cartilage and in arterial
vessel walls. Growth arrest-specific protein 6. GAS6
is secreted by leucocytes and endothelial cells in response to injury
and helps in cell survival, proliferation, migration, and adhesion.
Proline-rich Gla-proteins, transmembrane Gla-proteins, Gla-rich protein and
periostin; whose precise functions are still unexplored.
Health effects = Bone density=
Vitamin K2 deficiency results in a decreased level of active osteocalcin,
which in turn increases the risk for fragile bones. Research also showed that
vitamin K2, but not K1 in combination with calcium and vitamin D can decrease
bone turnover and that vitamin K2 is essential for the maintenance of bone
strength in postmenopausal women. The Japanese population seems to be at
lower risk for bone fractures compared to European and American citizens. This
finding would be paradoxical, if levels of calcium consumption were the only
factor determining bone density. Studies link Japan's greater levels of BMD to
that country's widespread consumption of natto. Increased intake of MK-7 from
natto seems to result in higher levels of activated osteocalcin and a
significant reduction in fracture risk. = Heart calcification=
Patients suffering from osteoporosis were shown to have extensive calcium
plaques, which impaired blood flow in the arteries. This simultaneous excess
of calcium in one part of the body, and lack in another – which may occur even
in spite of calcium supplementation – is known as the Calcium Paradox. The
underlying reason is vitamin K2 deficiency, which leads to significant
impairment in biological function of MGP, the most potent inhibitor of
vascular calcification presently known. Fortunately, animal research showed that
vascular calcification might not only be prevented, but even reversed by
increasing the daily intake of vitamin K2. The strongly protective effect of K2
and not vitamin K1 on cardiovascular health was confirmed by, among others,
Geleijnse et al. in the Rotterdam Study performed on a group of 4,800 subjects.
Results of more than 10 years of follow-up were verified, also by Gast et
al., who demonstrated that among K vitamins, the long-chain types of K2 are
the most important for efficiently preventing excessive calcium
accumulation in the arteries. Absorption profile of different K
vitamins Vitamin K is absorbed along with dietary
fat from the small intestine and transported by chylomicrons in the
circulation. Most of vitamin K1 is carried by triacylglycerol-rich
lipoproteins and rapidly cleared by the liver; only a small amount is released
into the circulation and carried by LDL and HDL. MK-4 is carried by the same
lipoproteins and cleared fast as well. The long-chain menaquinones are absorbed
in the same way as vitamin K1 and MK-4, but are efficiently redistributed by the
liver in predominantly LDL. Since LDL has a long half life in the circulation,
these menaquinones can circulate for extended times resulting in higher
bioavailability for extra-hepatic tissues as compared to vitamin K1 and
MK-4. Accumulation of vitamin K in extra-hepatic tissues has direct
relevance to vitamin K functions not related to hemostasis.
Dietary sources and adequate intake In 2012, Canadian health writer Kate
Rhéaume-Bleue suggested the Recommended Daily Allowance for K vitamins might be
too low. Earlier suggestions in the scientific literature, which note that
the RDA is based on hepatic requirements only, date back as far as 1998. This
hypothesis is supported by the fact that the majority of the Western population
exhibits a substantial fraction of undercarboxylated extra-hepatic
proteins. Thus, complete activation of coagulation factors is satisfied, but
there doesn’t seem to be enough vitamin K2 for the carboxylation of osteocalcin
in bone and MGP in the vascular system. Highest concentrations of vitamin K1 are
found in green leafy vegetables, but significant concentrations are also
present in non-leafy green vegetables, several vegetable oils, fruits, grains
and dairy. In Europe and the USA 60%, or more, of total vitamin K1 intake is
provided by vegetables, the majority by green leafy vegetables. National surveys
reveal that K1 intakes vary widely. Intakes determined by weighed-dietary
Intakes are similar in mainland Britain to the USA with average daily intakes of
around 70–80 μg, which is less than the adequate intake for vitamin K. Apart
from animal livers, the richest dietary source of long-chain menaquinones are
fermented foods typically represented by cheeses in Western diets and natto in
Japan. Food frequency questionnaire-derived estimates of
relative intakes in the Netherlands suggest that ~90% of total vitamin K
intakes are provided by K1, ~7.5 % by MK-5 through to MK-9 and ~ 2.5% by MK-4.
Most food assays measure only fully unsaturated menaquinones; accordingly
cheeses have been found to contain MK-8 at 10–20 μg/100g and MK-9 at 35–55
μg/100 g. Dietary intake sources
Vitamin K2 is preferred by the extra-hepatic tissues and this may be
produced as MK-4 by the animal from K1, or may be of bacterial origin. The
latter may be consumed already prepared by bacteria. Discussion is ongoing as to
what extent K2 produced by intestinal bacteria contributes to daily vitamin K2
needs. If, however, intestinal bacterial supply was enough to supplement all
tissues needing K2, we would not find high fractions of undercarboxylated
Gla-proteins in human studies.. Natural K2 is also found in bacterial
fermented foods, like mature cheeses and curd. The MK-4 form of K2 is often found
in relatively small quantities in meat and eggs. The richest source of natural
K2 is the traditional Japanese dish natto made of fermented soybeans and
Bacillus subtilis, which provides an unusually rich source of K2 as
long-chain MK-7: its consumption in Northern Japan has been linked to
significant improvement in K vitamin's status and bone health in many studies.
The intense smell and strong taste, however, make this soyfood a less
attractive source of K2 for Westerners' tastes. Supplement food companies sell
nattō extract, standardized for K2 content, in capsules. It is not known
whether B. Subtilis will produce K2 with other legumes.
Anticoagulants and K2 supplementation Recent studies found a clear association
between long-term anticoagulant treatment and reduced bone quality due
to reduction of active osteocalcin. OAC might lead to an increased incidence of
fractures, reduced bone mineral density/bone mineral content,
osteopenia, and increased serum levels of undercarboxylated osteocalcin. Bone
mineral density was significantly lower in stroke patients with long-term
warfarin treatment compared to untreated patients and osteopenia was probably an
effect of warfarin-interference with vitamin K recycling. Furthermore, OAC is
often linked to an undesired soft-tissue calcification in both children and
adults. This process has been shown to be dependent upon the action of K
vitamins. Vitamin K deficiency results in undercarboxylation of MGP. Vascular
calcification was shown to appear in warfarin-treated experimental animals
within two weeks. Also in humans on OAC treatment, two-fold more arterial
calcification was found as compared to patients not receiving vitamin K
antagonists. Among consequences of anticoagulant treatment: increased
aortic wall stiffness, coronary insufficiency, ischemia, and even heart
failure. Arterial calcification might also contribute to systolic hypertension
and ventricular hypertrophy. Coumarins, by interfering with vitamin K
metabolism, might also lead to an excessive calcification of cartilage and
tracheobronchial arteries. Anticoagulant therapy is usually
instituted to avoid life-threatening diseases and a high vitamin K intake
interferes with the anticoagulant effect. Patients on warfarin treatment,
or treatment with other vitamin K antagonist drugs, are therefore advised
not to consume diets rich in K vitamins. However, the latest research proposed to
combine vitamins K with OAC to stabilize the INR.
Toxicity There is no known toxicity associated
with high doses of menaquinones. Individuals taking anticoagulant
medications, such as warfarin should consult their doctor before taking
Vitamin K2. Unlike the other fat-soluble vitamins, vitamin K is not stored in any
significant quantity in the liver; therefore toxic level is not a described
problem. All data available at this time demonstrate that vitamin K has no
adverse effects in healthy subjects. The recommendations for the daily intake of
vitamin K, as issued recently by the Institute of Medicine, also acknowledge
the wide safety margin of vitamin K: “A search of the literature revealed no
evidence of toxicity associated with the intake of either K1 or K2”. A point of
concern is however the potential interference of K vitamins with OAC
treatment. Individuals taking anticoagulant medications, such as
warfarin should consult their doctor before taking Vitamin K2. Animal models
involving rats, if generalizable to humans, show that MK-7 is
well-tolerated. References