Vitamin K is called a coagulation vitamin because of its antihemorrhagic (hemostatic) effect, which was discovered in 1929 by physiologist and biochemist Carl Peter Henrik Dam on the basis of blood clotting studies. Vitamin K is not a uniform substance, but occurs in three structural variants. The following substances of the vitamin K group can be distinguished:
- Vitamin K1 – phylloquinone – occurring in nature.
- Vitamin K2 – menaquinone (MK-n) – occurring in nature.
- Vitamin K3 – 2-methyl-1,4-naphthoquinone, menadione – synthetic product.
- Vitamin K4 – 2-methyl-1,4-naphthohydroquinone, menadiol – synthetic product.
All vitamin K variants have in common that they are derived from 2-methyl-1,4-naphthoquinone. The main structural difference is based on the side chain in C3 position.While the lipophilic (fat-soluble) side chain in vitamin K1 has one unsaturated (with double bond) and three saturated (without double bond) isoprene units, vitamin K2 has a side chain with varying, usually 6-10 isoprene molecules. Vitamin K3, its water-soluble derivative menadione sodium hydrogen sulfite, and vitamin K4 – menadiol diester, such as menadiol dibutyrate – as synthetic products do not have a side chain. In the organism, however, covalent attachment of four isoprene units to the C3 position of the quinoid ring occurs. The methyl group on the quinoid ring in the C2 position is responsible for the specific biological efficacy of vitamin K. The side chain in the C3 position of the quinoid ring is the methyl group. The side chain in the C3 position, on the other hand, determines lipid solubility and thus influences absorption (uptake via the intestine). According to previous experience, about 100 quinones with vitamin K activity are known. However, only the naturally occurring vitamins K1 and K2 are of practical importance, since vitamin K3 and other naphthoquinones can exert adverse, sometimes toxic (poisonous) effects [2-4, 9-12, 14, 17].
Synthesis
While phylloquinone (vitamin K1) is synthesized (formed) in the chloroplasts (cell organelles capable of photosynthesis) of green plants, where it is involved in the photosynthetic process, the biosynthesis of menaquinone (vitamin K2) is carried out by various intestinal bacteria, such as Escherichia coli and Lactobacillus acidophilus, which occur in the terminal ileum (lower small intestine) and colon (large intestine), respectively. In the human intestine, up to 50% menaquinone can be synthesized – but only as long as a physiological intestinal flora is present. Intestinal resections (surgical removal of the intestine), inflammatory bowel disease (IBD), celiac disease and other intestinal diseases, as well as therapy with antibiotics such as cephalosporins, ampicillin and tetracyclines, can significantly impair menaquinone synthesis. Similarly, dietary changes due to alteration of intestinal flora may influence intestinal vitamin K2 synthesis. The extent to which bacterially synthesized vitamin K2 contributes to meeting requirements is controversial. Since, according to experimental experience, the absorption rate of menaquinone is rather low, it can be assumed that the synthesis performance of intestinal bacteria makes only a minor contribution to vitamin K supply. The observation that no vitamin K deficiency symptoms were found in subjects after a five-week vitamin K-free diet, but that these appeared after 3-4 weeks when antibiotics were administered at the same time, supports the assumption that vitamin K synthesized enterally (via the intestine) is indeed important for meeting requirements.
Absorption
There are major differences between the individual substances of the vitamin K group with respect to absorption. Dietary absorption is mainly phylloquinone. Alimentarily (with food) supplied or bacterially synthesized menaquinone plays a subordinate role in vitamin K supply.Like all fat-soluble vitamins, vitamins K1 and K2 are absorbed (taken up) during fat digestion, i.e. the presence of dietary fats as a means of transporting lipophilic molecules, bile acids for solubilization (increase in solubility) and micelle formation (formation of transport beads that make fat-soluble substances transportable in aqueous solution), and pancreatic lipases (digestive enzymes from the pancreas) for cleavage of bound or esterified vitamin K is necessary for optimal intestinal absorption (absorption via the intestine). Vitamins K1 and K2, as part of the mixed micelles, reach the apical membrane of the enterocytes (epithelial cells) of the jejunum (empty intestine) – phyllo- and menaquinone supplied by food – and terminal ileum (lower small intestine) – bacterially synthesized menaquinone – and are internalized. In the cell, incorporation (uptake) of vitamins K1 and K2 into chylomicrons (lipid-rich lipoproteins) occurs, which transport the lipophilic vitamins via the lymph into the peripheral blood circulation. While alimentary (dietary) vitamin K1 and K2 are absorbed via energy-dependent active transport following saturation kinetics, absorption of bacterially synthesized vitamin K2 occurs via passive diffusion.Vitamin K1 is rapidly absorbed intestinally (via the intestine) in adults with an absorption rate between 20 and 80%. In the neonate, the absorption rate of phylloquinone is only about 30% due to physiological steatorrhea (fatty stools). The bioavailability of lipophilic vitamins K1 and K2 depends on the pH in the intestine, the type and amount of dietary fats present, and the presence of bile acids and lipases from the pancreas (digestive enzymes from the pancreas). Low pH and short- or medium-chain saturated fatty acids increase, while high pH and long-chain polyunsaturated fatty acids inhibit the absorption of phyllo- and menaquinone. Since dietary fats and bile acids required for absorption are only available to a limited extent in the distal ileum (lower section of the small intestine) and colon (large intestine), where the vitamin K2-synthesizing bacteria are found, bacterial menaquinone is absorbed to a much lesser extent compared to phylloquinone. Because of their hydrophilicity (water solubility), synthetic vitamins K3 and K4 and their water-soluble derivatives (derivatives) are passively absorbed independently of dietary fats, bile acids, and pancreatic lipases (digestive enzymes from the pancreas) in both the small intestine and colon (large intestine) and released directly into the bloodstream.
Transport and distribution in the body
During transport to the liver, free fatty acids (FFS) and monoglycerides from chylomicrons are released to peripheral tissues under the action of lipoprotein lipase (LPL), which is located on cell surfaces and cleaves triglycerides. Through this process, chylomicrons are degraded to chylomicron remnants (low-fat chylomicron remnants), which, mediated by apolipoprotein E (ApoE), bind to specific receptors (binding sites) in the liver. Uptake of vitamins K1 and K2 into the liver occurs by receptor-mediated endocytosis.Phyllo- and menaquinone are partly accumulated in the liver and partly incorporated into hepatic (in the liver) synthesized VLDL (very low density lipoproteins; fat-containing lipoproteins of very low density). After release of VLDL into the bloodstream, absorbed vitamins K3 and K4 are also bound to VLDL and transported to extrahepatic (outside the liver) tissues. Target organs include kidney, adrenal gland, lung, bone marrow, and lymph nodes. Uptake of vitamin K by target cells occurs through lipoprotein lipase (LPL) activity. So far, the role of a specific menaquinone (MK-4) synthesized by intestinal bacteria and originating in the organism from phylloquinone and menadione is still unclear. In pancreas, salivary glands, brain and sternum a higher concentration of MK-4 could be found than of phylloquinone.Phylloquinone concentration in blood plasma is influenced by both triglyceride content and polymorphism of ApoE.Increased triglyceride serum concentration is associated with increased phylloquinone levels, which is observed more frequently with age. However, adults ≥ 60 years of age usually have poor vitamin K status, as evidenced by a low phylloquinone:triglyceride ratio compared with young adults.Polymorphism of ApoE (lipoprotein of chylomicrons) leads to structural changes in the protein, which prevents chylomicron remnants (low-fat chylomicron remnants) from binding to hepatic receptors. As a result, blood phylloquinone concentrations increase in addition to lipid concentrations, falsely suggesting a good supply of vitamin K.
Storage
Naturally occurring vitamins K1 and K2 are predominantly accumulated in the liver, followed by the adrenal gland, kidney, lungs, bone marrow, and lymph nodes. Because vitamin K is subject to rapid turnover (turnover) – about 24 hours – the storage capacity of the liver can only bridge a vitamin deficiency for about 1-2 weeks. Vitamin K3 is present in the liver only to a small extent, distributes more rapidly in the organism compared to natural phyllo- and menaquinone, and is metabolized (metabolized) more rapidly. The total body pool of vitamin K is small, ranging from 70-100 µg and 155-200 nmol, respectively. Studies on the bioavailability of phyllo- and menaquinone with healthy men have shown that after alimentary intake of similar amounts of vitamin K1 and K2, the concentration of circulating menaquinone exceeded that of phylloquinone by more than 10-fold. The reason for this is, on the one hand, the relatively low bioavailability of phylloquinone from food – 2-5-fold lower than that of vitamin K supplements – due to weak binding towards plant chloroplasts and low enteric release from the food matrix. On the other hand, menaquinone has a longer half-life than phylloquinone, and therefore vitamin K2 is available to extrahepatic tissues, such as bone, for a longer period of time.
Excretion
Vitamins K1 and K2 are excreted renally (via the kidney) in the form of glucuronides after glucuronidation by more than 50% in the bile with the feces (stool) and about 20% after shortening of the side chain by beta-oxidation (oxidative degradation of fatty acids). In parallel with phyllo- and menaquinone, vitamin K3 is also converted to an excretory form by the process of biotransformation. Biotransformation occurs in many tissues, especially in the liver, and can be divided into two phases:
- In phase I, vitamin K is hydroxylated (insertion of an OH group) by the cytochrome P-450 system to increase solubility.
- In phase II, conjugation with strongly hydrophilic (water-soluble) substances takes place – for this purpose, glucuronic acid is transferred to the previously inserted OH group of vitamin K with the help of glucuronyltransferase or a sulfate group by means of sulfotransferase, respectively
So far, of the metabolites (intermediates) and excretion products of vitamin K3, only 2-methyl-1,4-naphthohydroquinone-1,4-diglucuronide and 2-methyl-1,4-hydroxy-1-naphthyl sulfate have been identified, which, unlike vitamin K1 and K2, are rapidly and largely eliminated in urine (~70%). The majority of the metabolites of menadione have not yet been characterized.
