Vitamin K constitutes a family of compounds that exist as natural vitamin K1 (phylloquinone) and vitamin K2 (menaquinones) and the synthetic form vitamin K3 (menadionione). The chemical structure consist of a benzene ring (napthoquinone) and a side chain with various number of isopreny groups. The suffix numbers 4,7,8 and 9 refer to the position of these groups.
Vitamin K1 is the more prevalent form in our diet and is found in leafy green vegetables (lettuce, broccoli, cabbage, spinach etc) and vegetable oils. Vitamin K2 constitutes a family of compounds that include MK-4 and MK-7 forms that are rich in fermented foods like natto and various cheeses and the lesser available forms MK-8 and MK-9. Recent studies have suggested that vitamin K2 is better absorbed and persists longer in the plasma then vitamin K1 and may be more appropriate for supplementation.
Pharmacological functions:
The chief function of vitamin K is to act as a co-factor (an adjunct) for vitamin K-dependent proteins in the body and convert the glutamate residues of these proteins into gamma-carboxyglutamate group via an enzymatic process of carboxylation. Such proteins include coagulation factors (II,IV,VI and C), bone turnover molecules (osteocalcin and protein S), vascular repair proteins (Matrix GLA) and proteins responsible for cell-cycle arrest, signal transduction and cell-cell adhesion. The latter three proteins have implications in aberrant growth of cells e.g. tumorigenesis.
1. Bone Health
Bone is a living tissue that continually undergoes remodeling via synthesis and degradation of bone tissue by osteoblast and osteoclast cells respectively. In addition to other key nutrients for proper bone-remodeling e.g. calcium, vitamin D, vitamin C, zinc, magnesium and manganese, vitamin K plasma status is important for maintaining healthy bone. Osteocalcin is a small protein and the degree of its carboxylation (hence vitamin K status) is a measure of bone health. There is a direct correlation between carboxylation of osteocalcin and bone health. In human studies low serum vitamin K levels have been associated with increased incidence of osteopenia (pre-osteoporotic condition) and the full blown osteoporosis. Japanese studies have shown that in areas where there is high consumption of natto (Eastern Japan- Tokoyo) the incidence of osteoporosis and hip fractures is significantly low compared to Western Japan (Hiroshima) where the incidence of natto consumtion is low (hence low vitamin K levels).
2. Vascular Health
Arterial calcification shares many similarities with bone metabolism. Matrix GLA protein is found in vascular tissue. Under carboxylation of this protein (much like osteocalcin) is an indication of low plasma K levels and consequently the arterial tissue is less elastic due to increased calcium deposition resulting in increased incidence of cardiovascular mortality and ischemic heart disease. Studies have shown that vitamin K intake can have a protective effect and prevents loss of elasticity, a key indicator of vascular health. Furthermore, there is a recent clinical study from the UK which shows that vitamin K may protect not only against warfarin induced calcification but also may stabilize and help control anti coagulation levels. However, it is strongly advised that patients taking blood thinning medication like warfarin (Coumadin) should consult their physicians before taking vitamin K2.
3. Hepatocellular carcinoma
Studies have suggested that high levels of vitamin K intake may be associated with a lower incidence of one particular type of liver cancer (hepatocellular carcinoma). The mechanism is postulated to be an effect on inhibiting the cell-cycle, cell-cell adhesions (and possibly the ability to metastasize).
Menatetrenone, a vitamin K2 analogue, inhibits hepatocellular carcinoma cell growth by suppressing cyclin D1 expression through inhibition of nuclear factor kappaB activation.
Clin Cancer Res. 2007 Apr 1;13(7):2236-45.
Ozaki I, Zhang H, Mizuta T, Ide Y, Eguchi Y, Yasutake T, Sakamaki T, Pestell RG, Yamamoto K.
PURPOSE: Menatetrenone, a vitamin K2 analogue, plays an important role in the production of blood coagulation factors. Menatetrenone has also bee shown to have antineoplastic effects against several cancer cell lines including hepatocellular carcinoma (HCC) cells. However, the mechanisms by which vitamin K2 inhibits HCC cell growth have not bee fully clarified, and we therefore investigated the molecular basis of vitamin K2-induced growth inhibition of HCC cells.
EXPERIMENTAL DESIGN: HCC cells were treated with vitamin K2 and the expression of several growth-related genes including cyclin-dependent kinase inhibitors and cyclin D1 was examined at the mRNA and protein levels. A reporter gene assay of the cyclin D1 promoter was done under vitamin K2 treatment. The regulation of nuclear factor kappaB (NF-kappaB) activation was investigated by a NF-kappaB reporter gene assay, an electrophoretic mobility shift assay, a Western blot for phosphorylated IkappaB, and an in vitro kinase assay for IkappaB kinase (IKK). We also examined the effect of vitamin K2 on the growth of HCC cells transfected with p65 or cyclin D1.
RESULTS: Vitamin K2 inhibited cyclin D1 mRNA and protein expression in a dose-dependent manner in the HCC cells. Vitamin K2 also suppressed the NF-kappaB binding site-dependent cyclin D1 promoter activity and suppressed the basal, 12-O-tetradecanoylphorbol-13-acetate (TPA)-, TNF-alpha-, and interleukin (IL)-1-induced activation of NF-kappaB binding and transactivation. Concomitant with the suppression of NF-kappaB activation, vitamin K2 also inhibited the phosphorylation and degradation of IkappaBalpha and suppressed IKK kinase activity. Moreover, HCC cells overexpressing cyclin D1 and p65 became resistant to vitamin K2 treatment.
CONCLUSION: Vitamin K2 inhibits the growth of HCC cells via suppression of cyclin D1 expression through the IKK/IkappaB/NF-kappaB pathway and might therefore be useful for treatment of HCC.
Preventive effects of vitamin K on recurrent disease in patients with hepatocellular carcinoma arising from hepatitis C viral infection.
J Gastroenterol Hepatol. 2007 Apr;22(4):518-22.
Kakizaki S, Sohara N, Sato K, Suzuki H, Yanagisawa M, Nakajima H, Takagi H, Naganuma A, Otsuka T, Takahashi H, Hamada T, Mori M.
BACKGROUND: Despite the progression of therapeutic approaches, a high frequency of recurrence is what determines the long-term prognosis of patients with hepatocellular carcinoma (HCC). In this study, the chemopreventive effects of vitamin K2 on the recurrence and survival of patients with HCC after curative therapy were evaluated.
METHODS: Sixty patients who were diagnosed to be free of HCC after radiofrequency ablation therapy or surgery were randomly assigned to either the vitamin K2 group (n = 30 patients) or the control group (n = 30 patients). All patients were positive for the hepatitis C virus (HCV) antibody and hepatitis B surface antigen positive patients were excluded from this study. Patients in the vitamin K2 group received an oral dose of menatetrenone at 45 mg per day. Disease recurrence and the survival rates were analyzed in patients with HCC.
RESULTS: The cumulative recurrence-free rates in the vitamin K2 group were 92.3% at 12 months, 48.6% at 24 months and 38.8% at 36 months; and those in the control group were 71.7%, 35.9% and 9.9%, respectively (P = 0.045). The cumulative survival rates in the vitamin K2 group were 100% at 12 months, 95.0% at 24 months and 77.5% at 36 months; and those in the control group were 95.8%, 90.2% and 66.4%, respectively (P = 0.70).
CONCLUSIONS: Vitamin K2 may have a suppressive effect on the recurrence of HCC and a beneficial effect on tumor recurrence. However, there was no significant difference in the survival rates. The chemopreventive effects of vitamin K2 are not sufficient. The development of a further regimen such as combination therapy is required.
Vitamin K(2) supplementation improves hip bone geometry and bone strength indices in postmenopausal women.
Osteoporos Int. 2007 Jul;18(7):963-72.
Knapen MH, Schurgers LJ, Vermeer C.
Vitamin K mediates the synthesis of proteins regulating bone metabolism. We have tested whether high vitamin K(2) intake promotes bone mineral density and bone strength. Results showed that K(2) improved BMC and femoral neck width, but not DXA-BMD. Hence high vitamin K(2) intake may contribute to preventing postmenopausal bone loss.
INTRODUCTION: Vitamin K is involved in the synthesis of several proteins in bone. The importance of K vitamins for optimal bone health has been suggested by population-based studies, but intervention studies with DXA-BMD as a clinical endpoint have shown contradicting results. Unlike BMC, DXA-BMD does not take into account the geometry (size, thickness) of bone, which has an independent contribution to bone strength and fracture risk. Here we have tested whether BMC and femoral neck width are affected by high vitamin K intake.
METHODS: A randomized clinical intervention study among 325 postmenopausal women receiving either placebo or 45 mg/day of vitamin K(2) (MK-4, menatetrenone) during three years. BMC and hip geometry were assessed by DXA. Bone strength indices were calculated from DXA-BMD, femoral neck width (FNW) and hip axis length (HAL).
RESULTS: K(2) did not affect the DXA-BMD, but BMC and the FNW had increased relative to placebo. In the K(2)-treated group hip bone strength remained unchanged during the 3-year intervention period, whereas in the placebo group bone strength decreased significantly.
CONCLUSIONS: Vitamin K(2) helps maintaining bone strength at the site of the femoral neck in postmenopausal women by improving BMC and FNW, whereas it has little effect on DXA-BMD.
Menatetrenone (vitamin K2) and bone quality in the treatment of postmenopausal osteoporosis.
Nutr Rev. 2006 Dec;64(12):509-17.
Iwamoto J, Takeda T, Sato Y.
Menatetrenone (vitamin K2) reduces the incidence of vertebral fractures but has only modest effects on bone mineral density (BMD) in postmenopausal women with osteoporosis. Combined treatment with bisphosphonates and menatetrenone may be more effective than treatment with bisphosphonates alone in preventing vertebral fractures, despite the lack of an additive effect of menatetrenone on the BMD increase by bisphosphonates. Menatetrenone improves bone architecture in ovariectomized rats, and the mineral/ matrix ratio of the bone in terms of matrix volume and bone strength (without increasing bone mass) in rats with magnesium deficiency. Thus, available evidence supports an effect of menatetrenone on bone quality during osteoporosis treatment.
Beneficial effect of pretreatment and treatment continuation with risedronate and vitamin K2 on cancellous bone loss after ovariectomy in rats: a bone histomorphometry study.
J Nutr Sci Vitaminol (Tokyo). 2006 Oct;52(5):307-15.
Iwamoto J, Takeda T, Sato Y, Shen CL, Yeh JK.
The purpose of the present study was to examine the effect of pretreatment with risedronate and/or vitamin K2 and treatment continuation with reduced dosing frequency of the drugs on the early cancellous bone loss induced by ovariectomy (OVX) in rats. Eighty female Sprague-Dawley rats, 4 mo of age, were randomized by the stratified weight method into eight groups (n= 10 in each group); rats subjected to OVX, but not sham-operated rats, were treated with vehicle, risedronate, vitamin K2 (menatetrenone), or risedronate+vitamin K2 for 4 wk before the surgery, and the treatment was either discontinued (pretreatment groups) or continued after the surgery (treatment continuation groups) for 2 wk. Sham-operated rats (controls) were treated with the vehicle throughout the experimental period. During the 4 wk prior to the surgery (pretreatment), risedronate and vitamin K2 were administered five times a week either subcutaneously at a dose of 2.5 microg/kg body weight (risedronate) or orally at the dose of 30 mg/kg body weight (vitamin K2). During the 2 wk after the surgery (treatment continuation), the dosing frequency of the drugs was reduced to twice a week. Risedronate and vitamin K2 had an anti-resorptive effect on the bone. Pretreatment with risedronate alone, but not vitamin K2 alone, prevented the loss of the cancellous bone volume/total volume (BV/TV) of the proximal tibial metaphysis after OVX. Treatment continuation with vitamin K2 alone prevented the loss of the cancellous BV/TV after OVX, while treatment continuation with risedronate alone increased the cancellous BV/TV to beyond the values in controls. Pretreatment with risedronate+vitamin K2 had a more beneficial effect in increasing the cancellous bone mass than pretreatment with risedronate alone. Treatment continuation with risedronate and/or vitamin K_ appeared to have a more beneficial effect in increasing the cancellous bone mass than the respective pretreatment. Neither the total tissue area nor the cortical area of the tibial diaphysis was affected by any treatment. The present study demonstrated that pretreatment with risedronate had a beneficial effect on the early cancellous bone loss after OVX in rats, with a more beneficial effect when combined with vitamin K2. Moreover, even though the dosing frequency of the drugs was reduced after OVX, treatment continuation appeared to be more beneficial than pretreatment for increasing the cancellous bone mass.
Vitamin K2 treatment for postmenopausal osteoporosis in Indonesia.
J Obstet Gynaecol Res. 2006 Apr;32(2):230-4.
Purwosunu Y, Muharram , Rachman IA, Reksoprodjo S, Sekizawa A.
AIM: To investigate the effect of vitamin K2 (menatetrenone) treatment on bone mineral density (BMD) and a bone metabolic marker (osteocalcin) in postmenopausal women with osteoporosis living in Indonesia.
METHODS: A double-blind randomized placebo-controlled study of 63 postmenopausal women with osteoporosis. The vitamin K2 group (n = 33) received 45 mg menatetrenone and 1500 mg calcium carbonate per day and the control group (n = 30) received placebo and 1500 mg calcium carbonate per day for 48 weeks. BMD of lumbal spine (L2-L4), osteocalcin (OC) and undercarboxylated OC were measured before, 24 and 48 weeks after initiation of the treatment.
RESULTS: After 48 weeks of treatment, the mean percentage change of lumbar BMD in the vitamin K2 group was significantly higher (P < 0.05) than that of the control group. The undercarboxylated OC level decreased by 55.9% in the menatetrenone group and 9.3% in the control group compared with the baseline level. The difference between the two groups was significant (P < 0.01). The adverse events were three minor gastrointestinal cases, which subsided after temporary cessation of therapy.
CONCLUSIONS: Treatment with 45 mg vitamin K2 with 1500 mg calcium per day for postmenopausal women with osteoporosis for 48 weeks resulted in a significant increase in lumbar BMD and a significant decrease in undercarboxylated OC levels.
|
Recent News
AOR PMS Less - 180 vcaps CAD$ 33.55
AOR Vitamin D3 1000 - 60 vcaps CAD$ 12.85
AOR Vitamin D3 1000 - 120 vcaps CAD$ 15.55