On the Physiological Differences Between K2-MK4 and K2-MK7

This is a re-posting of a letter I wrote on an online forum for Osteoporosis.  It has been slightly edited for reasons of context.

***************

Hi, my name is Dr. Collin Cross.  I am a chemical physicist with specialties in structural molecular biology, biophysics, and rational drug design (a sort of specialized biochemist in short).  Pam XXXX originally invited me to join this group as one of the founding members because of my expertise and domain knowledge of vitamin K, specifically vitamin K2.  I have been reading the deep scientific and medical literature since 1988 and the literature specific to vitamin K2 since 2012.  In short, I have a large degree of both personal and professional knowledge of vitamin K2.  I have not been posting much recently due to other priorities but have decided to chime in on this topic once again.

The topic at hand is regarding the perpetual debate as to whether it is better to take, K2-MK4 or K2-MK7.  This debate is an old one and I have studied the science of it for a long time.  I’m chiming in here to make the case that for your total health, including osteoporosis (one of the best studied human aspects of K2), K2-MK4 is far superior to K2-MK7 for a fair number of different reasons.  I’ll elaborate on the various lines of evidence that show this a little later below.  Before I do that though, it is important to let people understand that the scientific literature surrounding K2 is very complex, and from my perspective, demonstrably tainted by commercial bias to a very large degree.  Additionally, this bias has only increased over the last 7-10 years as the market and learnings about K2 have increased, making it very difficult for lay persons, scientists, & doctors alike to unravel the tangled web.  In fact, I was confused for nearly a year after beginning to read the deep literature.  This was before it became clear what was going on.  When considering the lay literature, the situation is even worse.  People get their information from the internet and/or blogs then sometimes begin parroting all sorts of bad science based on bad premises and a limited understanding of physiology, structural biology, and the principles of biochemistry.  That said, as the details of the physiology of K2 become clearer, it gets easier to see the whole picture.  The commercial bias I am speaking of is due to the confluence of a few forces in the marketplace.  The primary contributing forces as I see them are 1) Canadian Regulatory Law, 2) the Soybean Industry, 3) Big Pharma, 4) Market Profiteers, 5) well-meaning experts and researchers who have not untangled the knot I’m describing and have it wrong.  I’ll explain each of the driving factors contributing to the commercial taint first and then move on to evidence supporting the superiority of MK4.

• Canadian Regulatory Law – When K2 biochemistry was in its early days of study it became clear that it was one of the most important hormones ( but regulated as a vitamin in North America like D) yet discovered due to its broad-based ability to impact so many different physiological pathways. Unfortunately, during this time, the Canadian Regulatory body decided to set a maximum threshold of 100 micrograms (mcg) per capsule for K2 supplements, thus limiting what can be legally manufactured and distributed in Canada, which is a very large fraction of the global market.  To this day, it is not legal to manufacture or distribute any supplement formula in Canada whose single serving contains more than 100 mcg of K2.  Luckily for the Canadian people, a 90-day supply of a formula with more can still be legally imported for personal use.  Because longer chain length menaquinones, like K2-MK7, cause side effects in most individuals at less than 100 mcg due to their poor cellular assimilation rates and subsequent inability to clear the plasma, this helps drive the subjective perception that K2-MK7 is more potent (efficacious) than K2-MK4.  In fact, the physiological fact of MK7’s longer ½ life in plasma is one of the main taglines used to tout MK7’s superiority to MK4.  It is said that the longer plasma (blood) ½ life equates to “better bioavailability” relative to MK4.  Unfortunately, this just isn’t true.  It sounds logical, but it is really evidence of quite the opposite, and I’ll speak more on that later.
• The soybean industry – Many people do not know that roughly 90% of the world’s “vegetable oil” is Soybean oil. Can you imagine how many soybeans are needed to supply 90% of the world’s vegetable oil, and how much money is involved?  How is soybean oil derived?  Primarily from cold pressing the soybeans themselves, leaving behind a crushed soybean husk as the primary industrial waste stream.  This means that huge piles of soybean husks are left over as waste when making Soybean oil.  As it turns out, MK7 can be economically made by the industrial fermentation of soybean husks and subsequent isolation of MK7, hence all the talk about Natto-derived MK7.  So as a Soybean oil manufacturer you can either a) pay to have someone haul off all these piles of rotten soybeans as waste, or b) develop a horizontal market to turn them into a high-margin product and then market aggressively to create a demand you can sell this product into.  In industry, we call this “horizontal integration”, and it is both very common and a very good business practice to support improved profitability for big business.
• Big Pharma – Did you know that Mk4 (but not MK7) has been shown to be able to help kill cancer and prevent its growth in over 15 different lines of cancer cells, including breast, leukemia, liver, and lung to name a few? Strangely, though, there are no human clinical trials.  Why might that be?  It also can help to cure a wide number of other ailments ranging from the skeleton, the nervous system, the immune system, the brain, diabetes, and many more.  In other words, some of the most common non-communicable diseases in the western world treated by prescription pharmaceuticals can be positively impacted by MK4.  This is a big money opportunity for the pharmaceutical industry, the single largest lobbying entity in the world that also has very deep pockets and advanced R&D operations.  If one studies the patent literature and other publications surrounding menatetrenone (MK4) it becomes possible to see a common direction being taken by many industrial research bodies.  It is more profitable for them to understand the mechanisms of the pathways that MK4 uses to work in the body and exploit them directly with novel drugs than it is to sell MK4 directly.  If the pathways and mechanisms are understood, it then becomes feasible to design a patentable high-margin pharmaceutical to impact these same pathways than it is to peddle MK4 which can be largely derived from the food chain itself or can be cost-effectively and conveniently supplemented.
• Market Profiteers – K2-MK7, either of biological or synthetic origin, can be purchased in bulk kilogram quantities for nearly the same cost as bulk K2-MK4. However, due to the high tendency for side effects for MK7 and the aggressive marketing literature, it is largely sold at about 1/5 – 1/10 of the active dosage per serving than MK4.  So, if MK4 and MK7 have the same bulk cost and MK7 is marketed at 1/5-1/10 the dosage, then this means a manufacturer can hitchhike on the existing marketing literature and sell 5-10 times the number of capsules for the same raw material cost of K2.  This makes Mk7 more profitable to sell.  It does not make it more potent or efficacious in the reversal of ailments.  In fact, the literature shows just the opposite.  This is one reason why MK4 is a prescription drug in Japan, where the bulk of the R&D has occurred, rather than MK7, even though Natto is a traditional Japanese food.  This does not mean that Mk7 (or MK5, Mk6, MK8, or Mk9 for that matter), doesn’t work.  It just means it doesn’t work as well).
• Well-meaning researchers with limited understanding – Scientists and Doctors are just like all types of people. Some are more diligent and knowledgeable than others.  It is easy for a Scientist or Doctor to fall victim to the same biased and convoluted literature as a layperson might.  This means they may mistakenly decide to research or advocate Mk7 rather than MK4 due to its growing popularity and unwittingly help to perpetuate the bias.

Now that I have outlined my perception of the landscape of commercial bias surrounding this market and influencing the debate of MK4 vs MK7, I’ll move on to the physiological evidence.   Unfortunately, deep scientific literature filled with the technical jargon of biology and chemistry is not easy to read.  I’ll try to simplify it as much as possible, but some independent study may be necessary to fully appreciate the topics I’ll elaborate on.   If you don’t want to read into some jargon that may be unfamiliar to many, it might be good to stop here.

One thing that is often misunderstood about scientific literature is that a) it is often not consistent and b) evolves over its history.  Therefore, one must take the time to read and understand the whole development of the literature to get a reasonable perspective.  One can’t simply cherry-pick a few papers of interest and expect to get a holistic understanding of the science.  One must understand things such as when one thing was proven, and another thing disproven, etc.  One must also be fluent in adjacent and related areas of chemistry and physiology to be able to draw proper conclusions from disparate and conflicting ideas and studies over time.  Then, unfortunately, when commercial bias creeps in, it takes the natural complications to a whole other level.  All that said here are some of the primary facts from studies of K2 properties that have been conclusively established and helped me to see the situation more clearly from a scientific perspective.

• MK4 is made from K1 in animal cells and MK7 is not

What is the difference between a hormone and a vitamin?  A good working definition is that both are metabolic co-factors that an animal will eventually die without.  However, the body can make a hormone via internal biosynthesis, whereas a vitamin must be procured from outside the body by diet or otherwise.  By this definition, K2-MK4 is a hormone.  This means it is made by the body from K1 found in vegetables and animal products and we will die if we run out.  On the other hand, MK7 is neither a hormone nor a vitamin as we will not die without it, and it is not made by the body.  MK7, like all the other long-chain Mkn’s (menaquinones), is a bacterial metabolite that shares some structural homology with MK4.  In the early days of study, MK4 was thought to be made in the GI tracts of animals via bacterial fermentation by inhabiting symbiotic microbes.  There were several problems with this hypothesis though that kept people searching.  It has now been firmly established that K2-MK4 is made by a wide variety of animal tissue cells by the direct conversion of K1 (phylloquinone) into K2-MK4 (menatetrenone).  This process is studied and measured by introducing deuterium labeled K1 into an animal’s diet and then looking for the same radio-labeled fragments in MK4 isolated from the same animal.  In nature, there is not much deuterium labeled K2-MK4 or K1.  So, if you feed labeled K1 to a rat and then find labeled K2 it is proof positive that the K1 was converted to K2.  Then by placing the label in different parts of the K1 molecule and then comparing where it lands in the K2, it is possible to understand more intricate parts of the chemical biosynthesis mechanism.  From here, however, the question becomes where did the conversation occur?  Was it bacteria in the GI tract, or was it in the animal cells themselves?  So, by performing this type of experiment on rats that have been fed powerful antibiotics that kill the GI microbiome and seeing that the conversion still occurs, it is proof that it is tissue cells that are doing the conversion, not GI bacteria.  Interestingly it has also been conclusively shown that MK4 assimilation and storage is tissue-specific, but I’ll talk more about that later.  However, by looking at how the radio-labeled K2-MK4 is distributed to various tissue cells over time it is possible to see which cells are using either greater or lesser quantities of MK4.  The most important point here is that no radio labeled MK7, or other longer chain menaquinones, are ever found during these experiments.  Meaning MK7 is not created in animal cells using vitamin K1 as a precursor, or by any other detected mechanism.  So, in summary, K2-MK4 is an animal hormone and MK7, or other MKn forms, are not.  Nor is MK7, or any other form of MKn with a chain length greater than MK4, essential for the life preservation of an animal.  The real question that evolves here is why? and how? would a human animal be more able to use MK7 than MK4 when it doesn’t even create it in the first place and it isn’t essential for life?  The answer is that it wouldn’t.  The experiments listed above and many more have been performed and conclusively show the situation I have described.   Here is one important reference to get those started that are interested in further study.  There is a whole line of such studies by multiple groups and they are very consistent.

https://pubmed.ncbi.nlm.nih.gov/9468334/

• MK4 is selectively produced and distributed within the tissues of the body in very specific ways, while the longer chain length menaquinones (MK5-MK9) are not

In addition to being made within the cells of the body from K1, MK4 is also selectively distributed and utilized in different ways by different tissues according to their various needs.  On the other hand, longer chain menaquinones (MK5-MK9) have been shown to accumulate primarily in the plasma (blood), liver (hepatic tissue cells), and other passive tissue compartments.  Using the same sort of radio-labeling experiments, both deuterium labeled K1 and deuterium labeled MK4 can be fed to animals and then various tissues can be analyzed to see how they take up (assimilate), store, and/or make MK4 via biosynthesis.  Many such experiments have been performed and are all very consistent.  Additionally, molecular markers for MK4 recycling can be studied to infer differing rates of MK4 usage in various cells in addition to the different assimilation rates.  While a complete discussion of this body of work and the wealth of conclusions it provides is beyond the scope of this article, the important points relative to the usage of MK4 vs MK7 in animals are that MK7 is not a) made by the body at all, and b) is not selectively assimilated and accumulated by various tissues in specific ways whereas MK4 is.  Again, this is because MK4 is a hormone essential for life that is used in animal tissue cells in a wide variety of very important and complex ways, whereas MK7 is not.  Therefore, we don’t see MK7 being selectively used, distributed, and accumulated in animal tissues in the same way.  Instead, MK5-9 primarily accumulate in the liver where they can be metabolized, with much more minor uptake by most other tissues.

http://www.ncbi.nlm.nih.gov/pubmed/8785182

https://pubmed.ncbi.nlm.nih.gov/14654717/

https://pubmed.ncbi.nlm.nih.gov/7947656/

https://pubmed.ncbi.nlm.nih.gov/9468334/

• MK4 passes the placenta and is found in human umbilical cord blood but MK7 is not

If MK7 were of use and/or important for the growth of fetal cells, wouldn’t we expect to find them in the blood passing to a fetus through the umbilical cord past the placenta?  In fact, a pregnant woman’s “placenta” is a selective barrier that allows necessary nutrients and gasses to pass to the fetus but can block certain things it recognizes as a problem.  According to a very interesting and pivotal experiment, a researcher collected paired samples from two groups of pregnant women.  The first group A) was fed a non-supplemented diet.  The second group B) was fed an MK7-rich diet via fermented soybeans (natto).  Then in both groups, maternal blood, maternal placenta, and umbilical cord blood were sampled.  As expected, the maternal blood and placenta of group B) contained much more long chain length menaquinones (MK6-MK9) than the A) group, while both groups showed similar concentrations of MK4 and K1.  The amazing thing is that only K1 and MK4 were found in the blood of the umbilical cord and the longer MKn’s were not detected at all.  This experiment conclusively shows that the placental barrier excluded the longer chain MKn’s, preventing them from passing but did allow both K1 and MK4 to pass to the fetus.  This is because as discussed above, both are necessary to animal life in very important ways, whereas MK7 is not.  In fact, MK7 has a very much higher rate of detrimental side effects, such as heart arrhythmia, than MK4 and these occur at much lower dosages.

https://www.sciencedirect.com/science/article/pii/S0892036217301769

https://pubmed.ncbi.nlm.nih.gov/3348316/

• MK7 is completely unable to upregulate several key bone growth factors

Bone growth is a very complex and balanced orchestra of sophisticated biochemistry.  Osteoporosis is a condition characterized by slower than normal “bone remodeling” rates.  Bone remodeling is a balance between the growth of new bone cells and the resorption of older bone cells.  Thus like all other tissues, bone is constantly turning over.  When its turnover rate becomes compromised, or unbalanced, osteoporosis can ensue as a result.  So how does the body know how to balance bone growth with bone resorption?  Well, it is a complicated multi-stage cellular process that, in part, proceeds under the influence of “bone growth factors” (also called nuclear growth factors) that are upregulated from the genetic code in a specific way.   In short, the body produces many important bone growth factors to control and regulate the bone growth process.  In a pivotal study, it was shown that MK7 was completely unable to upregulate several key bone growth factors, whereas MK4 was.  Now, this is very important.  To have the biggest and most holistic impact on health we want our cells to be able to upregulate ALL the factors it needs, not just some of them.  Following is a quote from the second reference below that clearly states the result.  “Among these up-regulated genes by MK-4, growth differentiation factor 15 (GDF15) and stanniocalcin 2 (STC2) were identified as novel MK-4 target genes independent of GGCX and SXR pathways in human and mouse osteoblastic cells. The induction of GDF15 and STC2 is likely specific to MK-4, as it was not exerted by another vitamin K₂ isoform MK-7, vitamin K₁, or the MK-4 side chain structure geranylgeraniol”.

In short, it is clearly shown that MK7 can’t upregulate all the same important cellular machines as can MK4.

https://pubmed.ncbi.nlm.nih.gov/8122528/

http://jme.endocrinology-journals.org/content/39/4/239.long

• MK4 is used to activate proteins inside the endoplasmic reticulum of cells, not in the blood. A longer ½ life in the blood means it is not being assimilated and used effectively.  As shown in the tissue distribution studies, it does not mean it is more “bioavailable”

One of the most common justifications touting the superiority of MK7 is that it has a “longer plasma half-life”.  Well, this at least is true.  The half-life of MK4 is roughly 4 hours, while MK7 is 12-14 hours, interestingly MK9 is on the order of 60 hours.  The longer ½ life, however, does not mean that these forms are more “bioavailable”, or more effective.  Quite the opposite.  MK4 is utilized deep inside the endoplasmic reticulum of cells where enzymes are biosynthesized after being upregulated for production at the genetic level.  This does not happen in the blood.  For any menaquinone to work, MK4, MK7, or any other variety, they must first get transported through the cell wall and into the endoplasmic reticulum.  The longer it is in the blood, the longer it takes to be put to work.  While the details of these mechanisms are very complex, they have nevertheless been largely understood for quite some time now.  However, as the tissue distribution and other studies show, MK4 is very selectively and effectively assimilated and distributed within the various tissues of the body and is not excluded from growing babies by the maternal placenta as is MK7.  It is also known to be used at different rates depending upon the different needs of various types of tissue cells.  In short, a quick half-life is a sign of effective assimilation and utilization.  The opposite is true of a longer half-life.  Once in the cell, K2-MK4 and K1 are efficiently recycled by a mechanism surrounding an enzyme called VKORC1 (Vitamin K epOxide Reductase Complex subunit 1).  This type of recycling mechanism is a means by which an animal can extend the use of a rare nutrient to buffer against times of shortage.  In nature, the availability of MK4 and K1 is not constant and so this buffering mechanism helps stabilize critical physiology on a daily basis even in times of scarcity.

http://www.bloodjournal.org/content/93/6/1798

In summary, MK4 has been much more widely studied from a biochemical perspective than MK7.  This is because it has been clear academically, at least to some, for a long time that MK4 is a specifically regulated and important hormone used and needed by the animal kingdom in a wide variety of very important ways.  The longer chain menaquinones are, instead, produced by bacteria for a much narrower and less complicated range of cellular functions in single-celled organisms.  As such, these longer chain MKn’s, including MK7, are much more widely available from food and while they do have some activity, they can’t accommodate the full range of animal needs and have much higher rates of side effects in many people.  While the longer chain menaquinones have weaker binding to animal protein receptor sites due to their longer chains, the shorter ones like MK5, MK6, Mk7, and MK9 can still partially activate some of the body’s cellular machinery.  However, because the longer chain menaquinones do not bind as ideally to animal receptor pockets they are not assimilated, transported, and used as effectively as is MK4 in humans and other animals.  This is clearly shown by the references above and is specifically why these larger forms have longer ½ lives in blood plasma.  This is simply because the body cannot use them as effectively, so they continue to circulate in the blood rather than being assimilated.  The longer the side chain, the longer the half-life.  Therefore, MK9 has a much longer serum ½ life even than MK7.  If a longer serum ½ life is indeed a good thing, we should then consider MK9 as a supplement rather than MK7 and see hordes of marketing literature working to convince us of that.  It is likewise available on the raw material market and has the same basic cost in bulk wholesale.  Only Mk7, however, is the economical product of horizontal integration in the food industry.  However, as I hope to have shown, a longer ½ life is not a good thing and we should stick to the compounds that are created by our body when it is in good health and has all the resources it needs.  What I do for myself is to supplement with high-quality MK4, eat an MK4-rich diet, and work to get a wide variety of longer chain menaquinones from foods.  Fermented vegetables and dairy are a rich source of most of the longer chain MKn’s.  Good cheeses, along with Kefir, and a variety of live fermented vegetables easily provide more than enough long chain MKn’s for my needs.