350 replies to this topic

[krillin]

This ensures that. Fortunately it's no longer the insane 10mg K-1 dose that could cause problems with selenium/glutathione (this info I got from Krillin, so ask him if you would like more info about it).

I don't recall finding a relationship with selenium. K1 reduces glutathione transferase activity, so I don't take any. All K's get metabolized to some extent to toxic menadione, so I take the minimum needed to get the desired effect, which means MK-7 and not MK-4. PMID: 19179058 found lower CHD risk in the Prospect-EPIC cohort mainly from MK-7, MK-8, and MK-9. I don't believe it was because MK-4 was lacking in their diets, because another study on this cohort reported MK-4 intakes higher than MK-7 and MK-8.

Semin Thromb Hemost. 1995;21(4):357-63.
Observations on vitamin K deficiency in the fetus and newborn: has nature made a mistake?
Israels LG, Israels ED.
Department of Medicine, University of Manitoba, Manitoba Institute of Cell Biology, Winnipeg, Canada.

The microsomal mixed function oxidase system metabolizes xenobiotics (Phase I) to products that, if not activated and conjugated for excretion (Phase II), are capable of forming conjugates with cellular macromolecules, including DNA, resulting in toxic, mutagenic, or carcinogenic events. Benzo(a)pyrene (BP), a polycyclic aromatic hydrocarbon, is a model carcinogen for this system. Vitamin K1 (phylloquinone) is a regulator of BP metabolism. These studies demonstrate that K1 is capable of increasing Phase I metabolism and decreasing glutathione transferase activity (Phase II) in chick embryo liver; that deprivation of K1 reduces BP/DNA adducts in mouse liver and reduces tumor formation in mice given intraperitoneal BP; and that K1 supplementation increases BP induced tumor formation in mice. However, epidemiologic studies indicate that children of mothers who smoke during pregnancy may not be at increased risk of cancer. It is known that the placentas from these pregnancies exhibit markedly increased levels of arylhydrocarbon hydroxylase induced by the polycyclic aromatic hydrocarbons in tobacco smoke, but there is no corresponding increase in this enzyme activity in the fetus in such pregnancies. We suggest that the low vitamin K level is a secondary protective mechanism for xenobiotics, such as BP, that may escape the primary placental screen. The recently described role of vitamin K-dependent Gla protein as ligands for receptor tyrosine kinases, also establishes K as a link in cell growth and transformation. It is proposed that the small total body pool of K1 in the adult, which is sufficient only to meet continuing needs, and the even smaller pool in the fetus are protective. This protective effect of low K1 levels is particularly important in the presence of the high mitotic rates and rapid cell turnover in the avian embryo and mammalian fetus.

PMID: 8747698

Br J Nutr. 2006 Feb;95(2):260-6.
Menadione is a metabolite of oral vitamin K.
Thijssen HH, Vervoort LM, Schurgers LJ, Shearer MJ.
Department of Pharmacology, Cardiovascular Research Institute Maastricht, University of Maastricht, PO Box 616, 6200 MD Maastricht, The Netherlands. h.thijssen@farmaco.unimaas.nl

Phylloquinone is converted into menaquinone-4 and accumulates in extrahepatic tissues. Neither the route nor the function of the conversion is known. One possible metabolic route might be the release of menadione from phylloquinone by catabolic activity. In the present study we explored the presence of menadione in urine and the effect of vitamin K intake on its excretion. Menadione in urine was analysed by HPLC assay with fluorescence detection. Urine from healthy male volunteers was collected before and after administration of a single dose of K vitamins. Basal menadione excretion in non-supplemented subjects (n 6) was 5.4 (sd 3.2) microg/d. Urinary menadione excretion increased greatly after oral intake of the K vitamins, phylloquinone and menaquinone-4 and -7. This effect was apparent within 1-2 h and peaked at about 3 h after intake. Amounts of menadione excreted in 24 h after vitamin K intake ranged, on a molar basis, from 1 to 5 % of the administered dose, indicating that about 5-25 % of the ingested K vitamins had been catabolized to menadione. Menadione excretion was not enhanced by phylloquinone administered subcutaneously or by 2',3'-dihydrophylloquinone administered orally. In archived samples from a depletion/repletion study (Booth et al. (2001) Am J Clin Nutr 74, 783-790), urinary menadione excretion mirrored dietary phylloquinone intake. The present study shows that menadione is a catabolic product of K vitamins formed after oral intake. The rapid appearance in urine after oral but not subcutaneous administration suggests that catabolism occurs during intestinal absorption. The observations make it likely that part of the menaquinone-4 in tissues results from uptake and prenylation of circulating menadione.

PMID: 16469140

Nutr Metab Cardiovasc Dis. 2009 Jan 27.
A high menaquinone reduces the incidence of coronary heart disease in women.
Gast GC, de Roos NM, Sluijs I, Bots ML, Beulens JW, Geleijnse JM, Witteman JC, Grobbee DE, Peeters PH, van der Schouw YT.

Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, The Netherlands; Department of Human Nutrition, Wageningen University, The Netherlands.

BACKGROUND AND AIM: Vitamin K dependent proteins have been demonstrated to inhibit vascular calcification. Data on the effect of vitamin K intake on coronary heart disease (CHD) risk, however, are scarce. OBJECTIVE: To examine the relationship between dietary vitamins K(1) and K(2) intake, and its subtypes, and the incidence of CHD. METHODS AND RESULTS: We used data from the Prospect-EPIC cohort consisting of 16,057 women, enrolled between 1993 and 1997 and aged 49-70 years, who were free of cardiovascular diseases at baseline. Intake of vitamin K and other nutrients was estimated with a food frequency questionnaire. Multivariate Cox proportional hazards models were used to analyse the data. RESULTS: After a mean+/-SD follow-up of 8.1+/-1.6 years, we identified 480 incident cases of CHD. Mean vitamin K(1) intake was 211.7+/-100.3mug/d and vitamin K(2) intake was 29.1+/-12.8mug/d. After adjustment for traditional risk factors and dietary factors, we observed an inverse association between vitamin K(2) and risk of CHD with a Hazard Ratio (HR) of 0.91 [95% CI 0.85-1.00] per 10mug/d vitamin K(2) intake. This association was mainly due to vitamin K(2) subtypes MK-7, MK-8 and MK-9. Vitamin K(1) intake was not significantly related to CHD. CONCLUSIONS: A high intake of menoquinones, especially MK-7, MK-8 and MK-9, could protect against CHD. However, more research is necessary to define optimal intake levels of vitamin K intake for the prevention of CHD.

PMID: 19179058

[krillin]

I spoke to AOR a while ago, and they told me that they used to have 3mg boron in the products, but that now it is not allowed anymore... Must be because it helps against arthritis, and pharma needs more money, always more. Notice now u got 700mcg of boron in the multi basics.... USELESS.

Do you have calculations to back this up? The best rationale I can see for boron is prostate cancer prevention. The lowest boron intake from diet is about 0.5 mg/day. To get into the protective highest quartile you need about 1.7 mg/day. Thus, to absolutely guarantee getting there you only need to supplement 1.2 mg/day. You need only a 0.7 mg supplement if your diet is 25th percentile or better, which should be a given if you're eating fruits, vegetables, and nuts. (I wish CRON-o-Meter included boron so I could dispense with the guessing.)

Boron's half life is only 21 hours, so I take half a 3 mg tablet daily.

Oncol Rep. 2004 Apr;11(4):887-92.
Dietary boron intake and prostate cancer risk.
Cui Y, Winton MI, Zhang ZF, Rainey C, Marshall J, De Kernion JB, Eckhert CD.
Department of Epidemiology, UCLA School of Public Health, Los Angeles, CA 90095-1772, USA. zfzhang@ucla.edu

Boron affects human steroid hormone levels. Circulating testosterone and estradiol levels have been proposed to modify prostate cancer risk. However, the association between dietary boron intake and the risk of prostate cancer has not been evaluated by any epidemiological study. We explored the association between dietary boron intake and the risk of prostate cancer in the USA. Our analysis was based on data from the third National Health and Nutrition Examination Survey (NHANES III). Cross-sectional case-control study design was employed by comparing boron intake of 95 prostate cancer cases with that of 8,720 male controls. After controlling for age, race, education, smoking, body mass index, dietary caloric intake, and alcohol consumption, increased dietary boron intake was associated with a decreased risk of prostate cancer with a dose-response pattern. The adjusted odds ratio was 0.46 (95% confidence interval: 0.21-0.98) for the highest quartile of boron intake comparing to the lowest quartile (P for trend = 0.0525). The observed association should be interpreted with caution because of the small case sample size and the nature of the cross-sectional study design, but deserve further investigation.

PMID: 15010890

[spacetime]

And they replied: "The amount is 120mcg because this is the maximum amount of vitamin K allowed by Health Canada".

<soapbox>I wonder which enlightened Canadian bureaucrat came up with that decree.</soapbox>


KILL.


I spoke to AOR a while ago, and they told me that they used to have 3mg boron in the products, but that now it is not allowed anymore... Must be because it helps against arthritis, and pharma needs more money, always more. Notice now u got 700mcg of boron in the multi basics.... USELESS.

This Canadian compliance is ridiculous. I wonder if they could produce a product for a non-Canadian market or are they bound to the guidelines given the product is manufactured there.

I asked them if they were going to switch to mk-7 and they said they had no plans to. Also inquired about the pitiful dose of resveratrol but they could provide no answer other than that's mroe than found in wine and it seems to exert a positive effect (french paradox).

[balance]

Most of what i've read on boron suggests 3-6mg is ideal. I don't have the links anymore as it was a long time ago. I also read something on how the levels in the soil in israel is the highest, and in jamaica is the lowest, and that in israel 5% had arthritis and in jamaica 90-95% and from there they suggested some dosing too.

I thought you told me that one of the enzymes of selenium was being inhibited by vitamin K1, but I guess you mean this instead. So this should resolve the MK-4 vs MK-7 deal at least for the time being? How much K1 is too much Krillin?

Are you aware of results like these?

http://www.nutraingr...-benefits-Study

K1 specifically.

[rwac]

All K's get metabolized to some extent to toxic menadione

Do you have a reference for that ?

[krillin]

All K's get metabolized to some extent to toxic menadione

Do you have a reference for that ?

That was from my second reference: "Menadione is a metabolite of oral vitamin K"

[krillin]

How much K1 is too much Krillin?

Are you aware of results like these?

http://www.nutraingr...-benefits-Study

K1 specifically.

That effect is not unique to K1. K2 fights inflammation and blood sugar too.

Int J Vitam Nutr Res. 2000 Dec;70(6):301-4.
Comparative effects of vitamin K2 and estradiol on experimental arteriosclerosis with diabetes mellitus.
Seyama Y, Kimoto S, Marukawa Y, Horiuchi M, Hayashi M, Usami E.
Department of Clinical Chemistry, Hoshi College of Pharmacy, 2-4-41 Ebara Shinagawa-ku, Tokyo 142-8501, Japan.

In order to further investigate the radical scavenging and anti-arteriosclerotic activities of vitamin K2 and estradiol, the comparative effects of vitamin K2 and estradiol on aortic calcium (Ca) and inorganic phosphorus (P) levels in the aorta and the elastin fraction (fr.) were investigated in male rats after experimental arteriosclerosis with diabetes mellitus was induced by vitamin D2 and radical producing substance, streptozotocin (STZ). Pharmacological dose of vitamin K2 (100 mg/kg b.w.) and medical dose of estradiol (83 micrograms/kg b.w.) suppressed the increased serum glucose, and vitamin K2 and estradiol increased the decrease in serum insulin. Moreover, vitamin K2 and estradiol inhibited the increase of Ca and P in the aorta and the elastin fr. Vitamin K2 and estradiol decreased the increase in serum lipid peroxide (LPO). It is suggested that both the pharmacological dose of vitamin K2 and medical dose of estradiol suppressed the development of arteriosclerosis associated with diabetes mellitus, owing to radical scavenging activity of vitamin K2 and estradiol.

PMID: 11214355

J Rheumatol. 2008 Mar;35(3):407-13.
Osteoclast inhibitory effects of vitamin K2 alone or in combination with etidronate or risedronate in patients with rheumatoid arthritis: 2-year results.
Morishita M, Nagashima M, Wauke K, Takahashi H, Takenouchi K.
Department of Joint Disease and Rheumatism, Nippon Medical School, Tokyo, Japan.

OBJECTIVE: To investigate the effects of vitamin K2 (Vit K2) alone or in combination with etidronate and risedronate on bone loss, osteoclast induction, and inflammation in patients with rheumatoid arthritis (RA). METHODS: Subjects comprised 79 patients with RA who were receiving prednisolone, divided into 3 groups: Group K, Vit K2 alone; Group KE, Vit K2 plus etidronate; and Group KR, Vit K2 plus risedronate. During a 24-month treatment and followup period, levels of N-terminal telopeptide of type I collagen (NTx) and bone alkaline phosphatase were measured. Bone mineral density (BMD) of the 3 groups was measured using dual-energy x-ray absorptiometry. Damage score to fingers on radiographic findings were measured according to the Larsen method. Serum levels of receptor activator of nuclear factor-kappaB ligand (RANKL) and osteoprotegerin (OPG) were measured. RESULTS: Falls in rate of change of BMD decreased after 18 months in groups KR and KE. Larsen damage scores indicated a significant difference between Group KE and other groups. Significant decreases in serum NTx were observed in groups KE and KR at all timepoints, but not in Group K. Levels of RANKL decreased significantly in all 3 groups. CONCLUSION: Vit K2 alone or in combination with bisphosphonates for treatment of osteoporosis in patients with RA may inhibit osteoclast induction via decreases in levels of RANKL.

PMID: 18260178

[krillin]

I wish CRON-o-Meter included boron so I could dispense with the guessing.

I found some boron food contents scattered over the internet, and it only took 1/4 cup almonds, 1/4 cup pecans, and 1/4 cup raisins to bring me above 3 mg, so even without a supplement I'm well above the 99th percentile. Woohoo! One less bottle!

[katzenjammer]

Very interesting post on Whole Health Source blog on recent dutch study on relationship to K2 & coronary heart disease: http://wholehealthso...d-coronary.html

[shifter]

As its not an either/or thing, I take both varieties. Especially given the cheap cost of 100mcg of the MK-7 anyway.

[kismet]

Very interesting post on Whole Health Source blog on recent dutch study on relationship to K2 & coronary heart disease: http://wholehealthso...d-coronary.html

I don't like his paleo bias and regularly disagree with some of his conclusions (although I can't comment on this blog entry yet). Just one thing: Why do paleo people always mention Masai? Who are they? As far as I know they live "healthy" but die early (or at least do not live extraordinarily long lives). I don't care. I'm life extensionist.

Edited by kismet, 10 March 2009 - 10:39 AM.

[JLL]

Very interesting post on Whole Health Source blog on recent dutch study on relationship to K2 & coronary heart disease: http://wholehealthso...d-coronary.html

I don't like his paleo bias and regularly disagree with some of his conclusions (although I can't comment on this blog entry yet). Just one thing: Why do paleo people always mention Masai? Who are they? As far as I know they live "healthy" but die early (or at least do not live extraordinarily long lives). I don't care. I'm life extensionist.

Because the Masai are an interesting example of a diet consisting solely of meat, milk and blood.

[VespeneGas]

http://wholehealthso...vitamin-k2.html

The saga continues. I am inclined to agree that we're more biologically accustomed (evolutionarily speaking) to the consumption of MK-4, but think it's premature to judge it superior to MK-7. I happen to supplement the latter (it's cheaper ) and eat eggs/hard cheeses for the former.

[krillin]

http://wholehealthso...vitamin-k2.html

The saga continues. I am inclined to agree that we're more biologically accustomed (evolutionarily speaking) to the consumption of MK-4, but think it's premature to judge it superior to MK-7. I happen to supplement the latter (it's cheaper ) and eat eggs/hard cheeses for the former.

Today, I found another difference between MK-4 and MK-7. I was reading a paper about SXR-independent effects of vitamin K2 on gene expression. The investigators found that MK-4 strongly activates transcription of two specific genes in osteoblast cells. Osteoblasts are cells that create bone tissue. The genes are GDF15 and STC2 and they're involved in bone and cartilage formation. They tested K1 and MK-7, and in contrast to MK-4, they did not activate transcription of the genes in the slightest. This shows that MK-4 has effects on gene expression in bone tissue that MK-7 doesn't have.

In vivo MK-7 turns into MK-4, so it'll activate those genes too.

J Bone Miner Metab. 1999;17(1):23-9.Click here to read Links
Effect of vitamin K2 (menaquinone-7) in fermented soybean (natto) on bone loss in ovariectomized rats.
Yamaguchi M, Taguchi H, Gao YH, Igarashi A, Tsukamoto Y.
Laboratory of Endocrinology and Molecular Metabolism, Graduate School of Nutritional Sciences, University of Shizuoka, Japan.

The effect of dietary vitamin K2 (menaquinone-7) on bone loss in ovariectomized (OVX) rats was investigated. OVX rats were freely given experimental diets containing menaquinone-4 (MK-4; 12mg/100g diet) or menaquinone-7 (MK-7; 18.1mg/100g diet) for 24 days; MK-4 and MK-7 were equal in molar concentrations. This feeding caused a remarkable increase of MK-4 and MK-7 concentrations in the serum and femur of OVX rats. OVX-induced decrease in the femoral dry weight and femoral calcium content was prevented by the feeding of dietary MK-4 or NK-7. In separate experiments, OVX rats were freely given experimental diets containing the fermented soybean (natto; including 9.4 microg MK-7/100g diet) without or with added MK-7 (37.6 microg/100g diet) for 77 days. Feeding produced a significant elevation of MK-4 and MK-7 concentrations in the serum of OVX rats. In this case, a significant increase in the femoral MK-4 content was observed but MK-7 was not detected in the femoral tissues. OVX-induced decreases in the femoral dry weight and femoral calcium content were significantly prevented by the feeding of diets containing natto with MK-7 added (37.6 microg/100g diets). This study demonstrates that the intake of dietary MK-7 has a preventive effect on bone loss caused by OVX. This effect may be partly caused by MK-4, which is formed by degradation of MK-7.

PMID: 10084398

[FunkOdyssey]

The combination of MK-7's uber long serum half-life and this new information suggests that MK-7 is a bit like a sustained release form of MK-4. The application of the 80/20 rule to Vitamin K supplementation demanded that I simply take the LEF combined MK-4/MK-7 supplement and stop worrying about it, but these nuances are interesting nonetheless.

[VespeneGas]

Krillin, is there evidence that this conversion takes place in humans too? Steven points out that the half-life of MK-4 and MK-7 are about the same in rats, which would seem to indicate rapid conversion and use, whereas in humans, MK-7's half life is many times longer than MK-4's.

Also, if MK-7 is converted to MK-4 in humans, wouldn't it's MK-4 activity be negligible given how little (90 mcg) we tend to supplement?

Believe me, I'd love to keep taking MK-7, I just want to understand the issue as thoroughly as possible.

[krillin]

The combination of MK-7's uber long serum half-life and this new information suggests that MK-7 is a bit like a sustained release form of MK-4. The application of the 80/20 rule to Vitamin K supplementation demanded that I simply take the LEF combined MK-4/MK-7 supplement and stop worrying about it, but these nuances are interesting nonetheless.

LEF's product also has a mg of K1, which as noted above increases phase I detox while suppressing phase II. I prefer not to think about all the damage I might have done to myself by taking their previous 10 mg version all those years.

[VespeneGas]

bump for your thoughts, krillin

[FunkOdyssey]

Semin Thromb Hemost. 1995;21(4):357-63.
Observations on vitamin K deficiency in the fetus and newborn: has nature made a mistake?
Israels LG, Israels ED.
Department of Medicine, University of Manitoba, Manitoba Institute of Cell Biology, Winnipeg, Canada.

The microsomal mixed function oxidase system metabolizes xenobiotics (Phase I) to products that, if not activated and conjugated for excretion (Phase II), are capable of forming conjugates with cellular macromolecules, including DNA, resulting in toxic, mutagenic, or carcinogenic events. Benzo(a)pyrene (BP), a polycyclic aromatic hydrocarbon, is a model carcinogen for this system. Vitamin K1 (phylloquinone) is a regulator of BP metabolism. These studies demonstrate that K1 is capable of increasing Phase I metabolism and decreasing glutathione transferase activity (Phase II) in chick embryo liver; that deprivation of K1 reduces BP/DNA adducts in mouse liver and reduces tumor formation in mice given intraperitoneal BP; and that K1 supplementation increases BP induced tumor formation in mice. However, epidemiologic studies indicate that children of mothers who smoke during pregnancy may not be at increased risk of cancer. It is known that the placentas from these pregnancies exhibit markedly increased levels of arylhydrocarbon hydroxylase induced by the polycyclic aromatic hydrocarbons in tobacco smoke, but there is no corresponding increase in this enzyme activity in the fetus in such pregnancies. We suggest that the low vitamin K level is a secondary protective mechanism for xenobiotics, such as BP, that may escape the primary placental screen. The recently described role of vitamin K-dependent Gla protein as ligands for receptor tyrosine kinases, also establishes K as a link in cell growth and transformation. It is proposed that the small total body pool of K1 in the adult, which is sufficient only to meet continuing needs, and the even smaller pool in the fetus are protective. This protective effect of low K1 levels is particularly important in the presence of the high mitotic rates and rapid cell turnover in the avian embryo and mammalian fetus.

I missed this one, ouch. I had thought K1 was basically useless (in comparison with K2) but also harmless. I was running out of the LEF product anyway, I guess I'll go back to Jarrow's MK-7.

Edited by FunkOdyssey, 13 March 2009 - 09:25 PM.

[yoyo]

The combination of MK-7's uber long serum half-life and this new information suggests that MK-7 is a bit like a sustained release form of MK-4. The application of the 80/20 rule to Vitamin K supplementation demanded that I simply take the LEF combined MK-4/MK-7 supplement and stop worrying about it, but these nuances are interesting nonetheless.

it sounds like it might have some similaries to vitamin D, where mk-7 acts as a provitamin for the more active form

[krillin]

bump for your thoughts, krillin

Some people are so impatient.

Krillin, is there evidence that this conversion takes place in humans too? Steven points out that the half-life of MK-4 and MK-7 are about the same in rats, which would seem to indicate rapid conversion and use, whereas in humans, MK-7's half life is many times longer than MK-4's.

I haven't found any solid proof that the MK-7 to MK-4 conversion occurs in humans.

Also, if MK-7 is converted to MK-4 in humans, wouldn't it's MK-4 activity be negligible given how little (90 mcg) we tend to supplement?

Below is the study he cites for MK-4 and MK-7 having the same half-life in rats. That didn't make it into the abstract, but it does say that uptake and loss by bone is a lot slower than for the liver, so I reason that only a small amount of K2 would be extracted from the blood stream before it heads back to the liver. But MK-4 liver clearance is fast so most of an MK-4 dose just gets wasted. It’s definitely possible that microgram doses of MK-7 raise bone MK-4 by as much as milligram doses of MK-4

The MK-4 vs MK-7 half-life difference might have something to do with how the Ks are carried in lipoproteins. The second paper below has some tantalizing details in the Google search results, like "MK-4 is mainly associated with the outer side of the lipoprotein particle" Someone needs to get it and report back. Rats and humans process lipoproteins differently, so that might explain why MK-7's half life isn't longer in rats. (Sheer speculation here.)

Br J Nutr. 2002 Apr;87(4):307-14.
Difference in the metabolism of vitamin K between liver and bone in vitamin K-deficient rats.
Sato T, Ohtani Y, Yamada Y, Saitoh S, Harada H.
Chemicals Research Laboratories, Honen Corporation, Iwata-gun, Shizuoka, Japan. tosato@honen.co.jp

The difference between vitamin K metabolism in the liver and that in the bone of vitamin K-deficient rats was examined. After 17 d administration of vitamin K-deficient food, vitamin K in the liver was almost depleted, and prothrombin time (PT) was prolonged. Serum total osteocalcin level was slightly decreased by vitamin K deficiency, whereas serum undercarboxylated osteocalcin level did not change. The level of menaquinone (MK)-4 as well as that of phylloquinone was decreased, but approximately 40 % of the initial level still existed in the femur after the 17 d period. A single-dose administration of vitamin K (250 nmol/kg body weight) markedly increased vitamin K level in the liver but not in the femur. These results suggest that the turnover of vitamin K in the bone is slower than that in the liver, and bone metabolism may be little affected by the short period of intake of vitamin K-deficient food. However, intake of a larger amount of vitamin K is required for its accumulation in the bone than in the liver. Furthermore, the counteracting effect of MK-7 on prolonged PT in vitamin K-deficient rats was found to be higher than phylloquinone or MK-4.

PMID: 12064340

Biochim Biophys Acta. 2002 Feb 15;1570(1):27-32.
Differential lipoprotein transport pathways of K-vitamins in healthy subjects.
Schurgers LJ, Vermeer C.
Department of Biochemistry and Cardiovascular Research Institute, Maastricht University, P.O. Box 616, 6200 MD, Maastricht, The Netherlands.

Vitamin K is a group name for K1 (phylloquinone) and K2 (menaquinones). Both forms contribute to the tissue vitamin K status. Following intestinal absorption, the serum transport of these lipophilic compounds to their target tissues takes place via lipoproteins. In previous studies we have found that K1 is preferentially accumulated in the liver, whereas menaquinones have a more widespread distribution pattern. Here we have tested whether these differences may be explained by the different liposolubility of the various K-vitamers, resulting in their association with different lipoprotein particles. Six healthy male volunteers received a mixture containing 2 micromol of each of three K vitamers (K1, MK-4, and MK-9) dissolved in corn oil. Blood was obtained at baseline and at different time intervals after intake for the measurement of vitamin K in serum and in the lipoprotein fractions. During the first 4 h after intake all K-vitamins were found to be associated predominantly with the triacylglycerol-rich lipoprotein (TGRLP) fraction. Since the TGRLP fraction is mainly cleared by the liver, this suggests that initially most of the K-vitamins are transported to the liver. In contrast to K1, however, both menaquinones investigated were also found in TGRLP and low-density lipoprotein, whereas MK-4 was even present in high-density lipoprotein. This explains why menaquinones may have a different distribution profile and suggests a relatively large impact of menaquinones on extra-hepatic vitamin K status than generally assumed. Moreover, the very long half-life time of MK-9 in the circulation indicates that it may form a more constant source of vitamin K than are either K1 or MK-4.

PMID: 11960685

[balance]

Krillin,

Check your inbox, I got the paper "MK-4 is mainly associated with the outer side of the lipoprotein particle" and sent it to you.


Looking forward to your thoughts/answers on this matter.

[krillin]

Check your inbox, I got the paper "MK-4 is mainly associated with the outer side of the lipoprotein particle" and sent it to you.

Excellent. The explanation is that only the most fat-soluble forms of K can reach the lipoprotein particle cores, which allows them to stay in circulation for several days. I pasted the most interesting parts below.

The fact that in all experiments the serum concentration of MK-4 reached its maximum well before that of K1 and MK-9 may result, therefore, from a quicker tissue uptake and clearance of MK-4 from the blood stream, whereas the very long half-life time for MK-9 points to a relatively slow tissue uptake of this vitamer. To provide an underlying mechanism for these observations we hypothesized that the different pharmacokinetic behaviour of the three vitamers is related to their different hydrophobicity: whereas the most water-soluble MK-4 may be packed relatively loosely, the highly lipo-soluble MK-9 may be present in the core of the lipoprotein particles, with an intermediate position for K1. This hypothesis was tested by measuring the vitamin K content of the various lipoprotein fractions.

Already in 1974 Shearer et al. showed that the major transport of vitamin K in plasma takes place via the TGRLP fraction [9]; recently this was confirmed by Lamon-Fava et al., who hypothesized that during the hydrolysis of triacylglycerol by lipoprotein lipase, K1 remains bound to the CR [12]. It is well known that after hydrolysis, the resulting fatty acids are readily taken up by endothelial cells, and the fact that the serum profile of MK-4 closely follows that of triacylglycerol in the TGRLP fraction suggests that MK-4 is taken up by the endothelium in parallel with the fatty acids. A similar principle has been reported for tocopherol [18. M.G. Traber, T. Olivecrona and H.J. Kayden J. Clin. Invest. 75 (1985), pp. 1729–1734. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (76)18]. During the formation of CR by LPL, excess surface components are transferred to HDL. The fact that – in contrast to the more hydrophobic K1 and MK-9 – at 2 h after ingestion MK-4 is already present in the HDL fraction, further supports the hypothesis that MK-4 is mainly associated with the outer side of the lipoprotein particle, where it is available for substitution. HDL on its turn can transfer such hydrophobic components to all other lipoproteins [19 and 20]. A second pathway for lipoprotein uptake of MK-4 would be the direct exchange from TGRLP to LDL, such as has been demonstrated for retinyl esters [21]. An alternative explanation for our observation that MK-4 peaks earlier in TGRLP than K1 does may be earlier and more efficient intestinal absorption, rather than quicker tissue uptake. In previous animal experiments MK-4 was absorbed substantially better than phylloquinone, when given in the same form [17]. Furthermore, the MK-4 present in the TGRLP fraction is rapidly cleared by the liver which than governs the MK-4 tissue distribution via its incorporation into lipoprotein particles. Such a mechanism was shown to be the case for vitamin E which has a specific binding protein in the liver cytoplasm. This protein preferentially binds α-tocopherol and incorporates this homologue into nascent VLDL, leading to a completely different lipoprotein profile for α-tocopherol and γ-tocopherol which differ only in a single methyl group. The minor structural difference results in a mainly extrahepatic distribution of α-tocopherol, whereas γ-tocopherol disappears rapidly from plasma by hepatic absorption, and is thought to be excreted via the bile [22]. Until now no vitamin K-receptor protein has been found on the cellular membrane, however. Only for MK-4 a nuclear vitamin K2 binding protein was reported to be present in human osteoblasts [23]. Further studies have to be conducted to test this hypothesis. With respect to clearance rate, Konishi et al. showed that 12 h after ingestion of 14C-labelled K1 or MK-4, only 9% of K1 and as much as 74% of MK-4 was excreted in the bile [24]. The authors concluded that MK-4 is much more extensively metabolized than K1. However, biliary excretion is often species specific and therefore cannot be extrapolated to humans.

In fasting serum low amounts of K1 were found in the LDL and HDL fractions, with only a slight increase during the postprandial period and peak values between 4–8 h after ingestion. It is at least plausible that some of the ingested K1 reaches these fractions by hepatic redistribution via the VLDL pathway [25]. These data suggest that the liver is the most important target tissue for vitamin K1, whereas relatively higher fractions of MK-4 accumulate in other tissues. But also in the latter case a dominant role for the liver cannot be excluded: it could be, for instance, that the liver is equally the initial target tissue for MK-4 but that its metabolism then differs from K1, including the possibility of a more rapid elimination of MK-4. This is consistent with previous data from our group demonstrating that K1 was 2–5-fold more efficient than MK-4 in counteracting vitamin K-deficiency induced hypoprothrombinaemia in rats [26], and that at equal intakes of K1 and MK-4 the former mainly accumulates in the liver, whereas MK-4 is preferentially absorbed by extra-hepatic tissues such as testis, pancreas, and kidney [10]. Also, the preferential utilization of K1 in the liver and MK-4 in the vessel wall supports the hypothesis of tissue specific uptake of K-vitamins [27]. However, one cannot exclude the capacity of some tissues to synthesize MK-4 from K1 [28 and 29]. Especially those tissues which accumulated preferentially MK-4 above K1, turned out to be capable of synthesizing their own MK-4 by conversion of K1 [11].

Like for K1, serum MK-9 concentrations reached a maximum at 4 h after intake. During the first 8 h MK-9 was exclusively found in the TGRLP fraction, suggesting that the liver is the main target tissue. A major difference with both short chain K-vitamers, however, was that MK-9 remained present in the circulation until the end of the experiment, whereas K1 and MK-4 had returned to baseline levels after 24 h. In a similar experiment (data not shown) MK-9 was even detectable at 72 h after intake. During this phase MK-9 was mainly found in LDL, which can survive in the circulation for several days. These data are compatible with an initial uptake of MK-9 by the liver, from where it is released slowly via LDL and remains available for all kind of tissues possessing LDL-receptors [30].

Taken together, our results show that the different lipophilicity of the various K-vitamers may result in substantial differences in their plasma transport and delivery to target tissues. The data provide an explanation for the previously observed preferential accumulation and utilization of K1 in liver and MK-4 in extra-hepatic tissues. Also, they provide an explanation for the data from a recent population-based study in which it was shown that long-term intake of menaquinones (notably the long-chain ones) is inversely correlated with arterial calcification, whereas for K1 intake the effect was much weaker [31].

[VespeneGas]

Fascinating. Thanks for your thoughts and work in this matter. Sorry I was impatient; I often feel that I cannot rest in such a situation until I believe that I've truly apprehended the nature and mechanism of a process like vitamin K metabolism.

Also reassuring is the inverse correlation between natto consumption and fracture risk

<h4 class="h4">Applied nutritional investigation </h4> Japanese fermented soybean food as the major determinant of the large geographic difference in circulating levels of vitamin K2: possible implications for hip-fracture risk




References and further reading may be available for this article. To view references and further reading you must purchase this article.

Masao Kaneki MD^a, Stephen J. Hedges PhD^b, Takayuki Hosoi MD^a, Saeko Fujiwara MD^c, Anthony Lyons FRCSEd^d, St. John Crean MBBS, FDSRCS^e, Nobuhiko Ishida MD^f, Mamoru Nakagawa BA^g, Masahiro Takechi BA^g, Yoshihisa Sano PhD^h, Yuzo Mizuno MD^a, Shinjiro Hoshino MD^a, Mariko Miyao MD^a, Satoshi Inoue MD^a, Kiyomi Horiki MSc^a, Masataka Shiraki MDⁱ, Yasuyoshi Ouchi MD^a and Hajime Orimo MD


Increasing evidence indicates a significant role for vitamin K in bone metabolism and osteoporosis. In this study, we found a large geographic difference in serum vitamin K2 (menaquinone-7; MK-7) levels in postmenopausal women. Serum MK-7 concentrations were 5.26 ± 6.13 ng/mL (mean ± SD) in Japanese women in Tokyo, 1.22 ± 1.85 in Japanese women in Hiroshima, and 0.37 ± 0.20 in British women. We investigated the effect of Japanese fermented soybean food, natto, on serum vitamin K levels. Natto contains a large amount of MK-7 and is eaten frequently in eastern (Tokyo) but seldom in western (Hiroshima) Japan. Serum concentrations of MK-7 were significantly higher in frequent natto eaters, and natto intake resulted in a marked, sustained increase in serum MK-7 concentration. We analyzed the relation between the regional difference in natto intake and fracture incidence. A statistically significant inverse correlation was found between incidence of hip fractures in women and natto consumption in each prefecture throughout Japan. These findings indicate that the large geographic difference in MK-7 levels may be ascribed, at least in part, to natto intake and suggest the possibility that higher MK-7 level resulting from natto consumption may contribute to the relatively lower fracture risk in Japanese women.

[wolfeye]

What's the quality of the Menaquinone-7 (Mk7) from Vitalprimelabs.com?
How many mcg of Menaquinone-7 do you get out their extracts 1300ppm and 2500ppm 100 gram packages?

[stephen_b]

Like for K1, serum MK-9 concentrations reached a maximum at 4 h after intake. During the first 8 h MK-9 was exclusively found in the TGRLP fraction, suggesting that the liver is the main target tissue. A major difference with both short chain K-vitamers, however, was that MK-9 remained present in the circulation until the end of the experiment, whereas K1 and MK-4 had returned to baseline levels after 24 h. In a similar experiment (data not shown) MK-9 was even detectable at 72 h after intake. During this phase MK-9 was mainly found in LDL, which can survive in the circulation for several days. These data are compatible with an initial uptake of MK-9 by the liver, from where it is released slowly via LDL and remains available for all kind of tissues possessing LDL-receptors [30].

I'm wondering if there are tissues that do not have LDL-receptors that can benefit from MK4 but not MK9.

StephenB

[krillin]

I'm wondering if there are tissues that do not have LDL-receptors that can benefit from MK4 but not MK9.

Both of them are delivered by TGRLP, so I don't see how MK-4 could go somewhere that MK-9 can't.

[stephen_b]

Has anyone noticed softer facial skin and disappearance of dental plaque on just MK-4? I've noticed both on MK-4. (Sorry, I don't know how much MK-4; I was using two caps of this product, which also contains 10k IU of vitamin A, but others have noticed the same thing with 1-2 mg of the Thorne K2 drops).

Both changes are quite obvious.

Stephen

edit: I should have written "Has anyone noticed softer facial skin and disappearance of dental plaque on just MK-4?"

Edited by stephen_b, 16 April 2009 - 01:05 PM.

[katzenjammer]

Has anyone noticed softer facial skin and disappearance of dental plaque on just MK-7? I've noticed both on MK-4. (Sorry, I don't know how much MK-4; I was using two caps of this product, which also contains 10k IU of vitamin A, but others have noticed the same thing with 1-2 mg of the Thorne K2 drops).

Both changes are quite obvious.

Stephen

I've been thinking of posting the exact same question. The effects are quite noticeable. I was just at the dentist - I go every three months for cleaning because of huge plaque build up on bottom front teeth. Even after only three months I have quite a bit. This time she said, "ummmm, there's nothing to clean."

[ajnast4r]

Bump... I can't decide on a good dose. 50 of 100 mcg, every day? Every other day?