Both vitamin K1 and vitamin K2 are fat soluble vitamins, which are essential bioactive substances for human body. Both are coenzymes of γ-glutamyl carboxylase. However, due to the different molecular structure of vitamin K1 and vitamin K2, their absorption rate, tissue distribution, bioavailability and health effects are different. Vitamin K1 promotes the activation of coagulation factors II, VII, IX, X and has the effect of promoting coagulation; while vitamin K2 has the effect of activating osteocalcin, promoting energy release, treating osteoporosis, preventing arteriosclerosis and organ calcification and other health effects. Therefore, we compare the differences between vitamin K1 and K2 from different aspects.

1.Structural differences between vitamin K1 and vitamin K2

　　The difference of the chemical structure between vitamin K1 and K2 is reflected in the difference of the side chains at #3 carbon of the menaquinones rings. Vitamin K1 has an aliphatic side chain which has only one C=C bond, while K2 is a polymerized side chain with multiple isoprene units^[1]. Therefore, the saturated alkanes part of K1 can rotate freely, while K2 has strong rigidity, and there are cis- and trans- isomers of vitamin K2. Among them, only trans-vitamin K2 has biological activity. Polyisoprene is terpenoid, so from the side chain’s point of view, vitamin K2 can also be categorized as terpene species, therefore MK-4 is a diterpene and MK-7 is a triploid semiterpene. But vitamin K1 is not terpene. In a word, there are great structural differences between vitamin K1 and K2, which will also affect their biological activities.

2.Differences in dietary sources of vitamin K1 and vitamin K2

　　Vitamin K1 is the main form of vitamin K in the diet^[2,3]. It mainly exists in green vegetables and green leaves, including spinach, cabbage, kale, etc., as well as avocado, kiwi fruit, grape and other fruits^[4,5]. The absorption of vitamin K1 depends on fat soluble foods such as butter or oil. Vitamin K1 is the end product of shikimate pathway in photosynthesis of plant. Therefore, vitamin K1 can be found in all photosynthetic organisms (including plants, algae and cyanobacteria)^[6,7].
　　Vitamin K2 is mainly synthesized by bacteria^[8] and exists in fermented foods^[1,9], such as fermented bean products, meat and dairy products^[10]. The content of vitamin K2 (especially MK-7) in natto fermented by Bacillus subtilis was up to 10985 ng/g, while the content of vitamin K1 was only 321 ng/g^[11]. Dairy products are the second richest source of vitamin K2 in diet, and the content of vitamin K2 in hard cheese is relatively high^[12]. Other sources of vitamin K2 are chicken, egg yolk, pickles, beef and salmon^[10]. In addition, in animal’s body, vitamin K2 (MK-4) can be transformed from vitamin K1 by tissue-specific transformation. This reaction is catalyzed by UbiA isopentenyltransferase domain containing one enzyme^[13] and menaquinones is an involved intermediate. In fact, there are high portion of MK-4 in animal is from vitamin K1^[14]. This suggests that vitamin K1 taken by herbivores from green leaves can be converted into vitamin K2 in vivo, which performs physiological functions that K1 cannot achieve. This is of great significance in the process of survival and evolution of species. It is also suggested that as the upper part of the food chain, the balanced intake of animal and vegan products is of great significance to supplement vitamin K1 and K2 necessary for life support activities. At the same time, vegetarians must intake fermented food to ensure their health.

Table 1　Comparison of dietary sources of vitamin K1 and vitamin K2

3.Pharmacokinetic differences between vitamin k1 and vitamin k2

　　A comparative study found that after intake of food that rich in vitamin K1 or vitamin K2 (MK-7), both of vitamin K1 and vitamin K2 (MK-7) were easily absorbed, but their bioavailability was different. The concentration of postprandial serum vitamin K2 (MK-7) was 10 times higher than that of vitamin K1^[2]. Besides, vitamin K1 showed significant individual differences in fasting plasma^[15]. The absorption rate of vitamin K1 was lower than that of MK-4 and long-chain vitamin K2, especially MK-8 and MK-9 from food sources^[2]. The cycle half-life of long-chain vitamin K2 (MK-7 and mk-9) is longer than that of vitamin K1^[16]. Therefore, MK-7 absorbed by extrahepatic tissues has a long time in circulation^[11]. However, not all vitamin K2 uptake is the same. Among all vitamin K2 derivatives, MK-7 has the highest absorption efficiency and the highest bioavailability^[2,11]. After oral administration of MK-7, the level of serum MK-7 was increased and could last for several days, thus contributing to its biological effect^[16]. Although the half-life of MK-9 is longer, its bioavailability is not high^[17], suggesting that MK-9 may have greater affinity for adipose tissue.
　　All members of the vitamin K family can be absorbed by intestinal epithelial cells and enter chylomicrons in the absorption process. Then, after entering the circulation with lymph, the chylomicrons are transported to their respective target cells by lipoproteins^[17,18]. Vitamin K1 is mainly transported by triglyceride rich lipoproteins, and vitamin K2 is mainly transported by LDL. Vitamin K1 has a half-life of 1-2 hours, while MK-7 has a half-life of 68 hours^[11]. Meanwhile, these vitamin K1 chylomicrons can be rapidly removed from the circulation, and vitamin K1 is accumulated in the liver^[17]. Isotopic labeling shows that vitamin K1 is quickly removed from the blood circulation after intake, and its metabolites are rapidly present in urine and bile^[19,20]. It is suggested that vitamin K1 is excreted from urine and bile after its function in the liver is completed.
　　However, vitamin K2, especially long-chain derivative (MK-7), can form a circulation between LDL and blood. By repeatedly distributing K2 into circulation, it can reach extrahepatic tissues, such as bone and vascular system^[1,17]. The target cells took longer time to take vitamin K2 than to take vitamin K1. In fact, cross clinical studies with equal amounts of vitamin K1 and K2 shows that subjects in the MK-7 group had higher levels of carboxyosteocalcin than those in the vitamin K1 Group^[11]. In another cross study of the same study population, the effect of MK-7 on counteracting coumarin anticoagulant was almost three times that of vitamin K1^[11]. This also explains that vitamin K2 supplementation rather than vitamin K1 supplementation can affect the risk of cardiovascular disease^[21].

4.The content difference of vitamin K1 and vitamin K2 in human body

　　When testing the serum levels of vitamin K1, MK-4 and MK-7 in people of different areas, it can be found that except for kidney transplant patients in Netherlands and young people in British, the MK-7 content in most of the collected population is higher than that of vitamin K1. The low content of MK-4 in each population indicates that the endogenous production of MK-4 is low. Through comparison, we found that the serum content of MK-7 in Japanese was significantly higher than that in other populations, which may be related to their regularly intake of natto food.

Table 2　Comparison of vitamin K1 and vitamin K2 in human serum

5.Difference of health effects between vitamin K1 and vitamin K2

　　The therapeutic value of vitamin K2 for heart and vascular diseases is irreplaceable. The famous Rotterdam study shows that 4807 subjects without myocardial infarction at baseline have been followed up for 7 years, resulting in a low level of vitamin K2, rather than vitamin K1, reduces the risk of coronary heart disease and severe aortic calcification by 50% and all-cause mortality by 25%^[21]. In a prospective EPIC cohort study, 16057 women without cardiovascular disease at baseline were followed up for an average of 8.1 years. The results showed that there was a significant negative correlation between vitamin K2 intake (especially MK-7, MK-8 and MK-9) and the risk of coronary heart disease. Moreover, for every 10 μ g increase in vitamin K2 intake, the risk of coronary events decreased by 85% - 100%^[22]. Similarly, some studies have shown that vitamin K1 intake has no significant correlation with the prognosis of cardiovascular disease ^[22,23].
　　Vitamin K group compounds act as coenzymes of γ - glutamic acid carboxylase (GGCX), which is responsible for carboxylation of glutamate residues of vitamin K-dependent proteins (VKDPs) to form a calcium binding γ-carboxylated glutamate residue (Gla)^[24,25]. There are at least 17 kinds of VKDPs in human body, also known as gla proteins, which have been identified as intrahepatic VKDPs and extrahepatic VKDPs according to the synthesis site. VKDPs synthesized in the liver are necessary for the regulation of coagulation, including coagulation factors II, VII, IX, X, and anticoagulant proteins C, S and Z. VKDPs synthesized in the liver include matrix Gla protein (MGP), osteocalcin (OC), Gla rich protein (GRP), growth inhibition specific protein 6 (Gas6), proline rich Gla protein (PRGP1 and PRGP2), transmembrane gla protein (TMG3 and TMG4) ）, periosteal protein and γ- glutamyl carboxylase. The main health effects of these extrahepatic VKDPs are multiple organ protective effects, such as bone homeostasis, ectopic calcification, cell differentiation and proliferation, inflammation and signal transduction, which focus on the protection of bone and cardiovascular system. γ-carboxylation showed the necessary conditions for VKDPs to have health effects. In addition, vitamin K2 deficiency is significantly related to some pathological conditions, such as cardiovascular disease, chronic kidney disease (CKD)^[26], osteoarthritis (OA)^[27], rheumatoid arthritis (RA), osteoporosis, cancer, dementia, some skin pathology, functional decline and disability^[29].
　　In contrast, the health effect of vitamin K1 is to act as a cofactor in the activation of related clotting factors^[29,30]. Vitamin K1, through the activation of glutamic acid (Glu) residues in coagulation factors II, VII, IX and Ⅹ, makes these factors form a high affinity binding with negatively charged phospholipid membrane area under the support of calcium. Thus the hemostatic effect of coagulation factors can be achieved^[31,32,33].
　　As well-established guidelines have been developed, vitamin K1 can be used as a drug. For example, take 1 mg of vitamin K1 shortly after birth to prevent potentially fatal vitamin K deficiency bleeding. Bleeding within 24 hours of birth is uncommon and is usually caused by medication taking by the mother. These drugs may interfere with fetal vitamin K metabolism^[34]. Without prophylactic administration of vitamin K1, this bleeding can occur in the first week of birth. Due to inadequate placenta metastasis and low vitamin K concentration in human milk^[35,36], vitamin K deficiency is caused. In addition, vitamin K1 is used as an antagonist in the treatment of patients before elective surgery or when the international standardized ratio is too high (continuous bleeding). But the effect of vitamin K1 on osteoporosis and artery calcification is very weak.
　　In conclusion, due to the differences in the main structure of vitamin K1 and vitamin K2, their absorption rate, tissue distribution, bioavailability and health effects are different, which leads to the differences in health effect. Vitamin K1 promotes hemostasis; while vitamin K2 has the following effects: ① preventing osteoporosis and fracture, improving bone development; ② preventing vascular calcification, preventing atherosclerotic diseases; ③ help to prevent and cure cancer; ④ help to prevent and cure chronic kidney disease; ⑤ help to prevent and cure diabetes, and so on. However, vitamin K2 (MK-7) had no significant effect on coagulation function in normal dosage.

Table 3　Effect of vitamin K1 and vitamin K2 on coagulation index

Compared with the control group *p<0.05，**p<0.01

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