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Vitamin K Group
Several compounds have vitamin K activity, all naphthoquinones. Phylloquinone consists of a naphthoquinone ring attached to a phytyl side chain. Vitamin K1 was named phylloquinone and phytonadione, referring to plant origin. Other K vitamins are based on menaquinone (2-methyl-1,4-naphthoquinone ). Bacteria synthesize a variety of menaquinones, often found in fermented foods. The best known function of the K group is to act as cofactors for g-carboxylation of vitamin K-dependent proteins. These include clotting factors, ostocalcin and matrix Gla protein.
Different carbon side chains on the naphthoquinone rings create distinctly different molecules with differing biological activities. A naming system uses MK and a carbon chain number, such as MK-2, to describe the different molecular groups. Differences in the isoprenoid side chain alter transportation, uptake and excretion. Phylloquinone is transported by lipoproteins. MK-4 is synthesized in tissues from phylloquinone. Both phylloquinone and MKs activate the steroid and xenobiotic receptor that initiates their catabolism.
K1 is an essential for the carboxylation of liver proteins, required for blood coagulation: prothrombin, factors VII, IX, and X. The best known function is the formation of prothrombin; deficiency causes a bleeding disorder. Newborn infants tend to be deficient in Vitamin K1; intramuscular administration shortly after birth has become standard practice. Vitamin K1 is added to infant formulas. The microflora in the digestive tract syntheses different vitamin Ks, supplying a portion of the daily requirement. If dietary intake is low and microflora are reduced by antibiotic administration, deficiency results. Warfarin (Coumadin), an anticoagulant drug, blocks vitamin K recycling, causing a drop in the clotting factor, prothrombin. since dietary intake of K1 varies, a daily supplement of phylloquinone has shown potential for stabilizing anticoagulation control.
K1 is obtained by eating green plants and vegetable oils. One serving of spinach or collards and two servings of broccoli provide five times the RDA of about 90 to 120 micrograms per day. Soybean, canola and olive oil are second best sources. When these oils are hydrogenated to form solid fats such as margarine, K1 is converted to dihydrophylloquinone (DHK1). Fast foods contain DHK1 with little or no K1.Weizmanna et al analyzed the Vit K1 content of fast foods consumed in the US. They expressed concern that differences K1 and DHK1 in their biological activity complicates nutrient analysis and may be a concealed health hazard. Phylloquinone is converted to menaquinone-4 (MK-4) in tissues. Booth et al demonstrated in rats that dihydrophylloquinone intake reduces MK-4 in certain tissues: lower levels were found in kidney, heart, testes, cortex (myelin), and striatum (myelin). Other non-cofactor functions of vitamin K include the suppression of inflammation, prevention of brain oxidative damage and a role in sphingolipid synthesis.
Vitamin K2 : MK-4 and MK-7
All K vitamins are similar in structure, but differ in the length of the “side chain”. The longer the side chain, the better effect and efficiency. Consequently, the long-chain menaquinones (especially MK-7) are the most desirable as they are nearly completely absorbed (body requires smaller doses) and stay in the blood for the longest time. There are three forms of K vitamins presently available in dietary supplements; synthetic vitamin K1, synthetic menaquinone-4 (MK-4) and natural vitamin K2 as menaquinone-7 (MK-7). Recent studies show that natural vitamin K2 as MK-7 is consistently found to be more effective compared to both vitamin K1 and MK-4
There are benefits for increased intake of MK-2 and MK-7 to prevent and treat osteoporosis and arterial calcification. In studies supplemental dose ranged from 100 micrograms to 50 milligrams per day. The Japanese fermented soya bean mix, Natto, had the highest MK-7 levels in a small sample of foods that were tested. MK-7 is more effective than phylloquinone in carboxylating both liver and bone Gla proteins
Vitamin K deficiency is associated with low bone mineral density and increased risk of bone fracture. Arterial calcification and osteoporosis occur frequently in postmenopausal women. While osteocalcin is the main target for Vit K activity, matrix Gla protein (MGP) synthesized by chondrocytes and vascular smooth muscle cells, inhibits tissue calcification, but requires carboxylationto function. Arterial calcification occurs both in the media and the intima or arterial walls. Medial calcification (Mönckeberg's arteriosclerosis) is independent of atherosclerosis. MGP is expressed at both sites. Increased MGP expression in vascular smooth muscle is a potent inhibitor of vascular calcification. Extensive arterial calcification was found in animals that do not express carboxylated MGP
Shiraki et al measured the circulating concentrations phylloquinone (K1) and menaquinones (MK-4) and (MK-7) in 396 Japanese women and related these results with osteocalcin, calcium, and phosphorus; bone-derived alkaline phosphatase activity. They found that ostocalcin activity was increased by higher K1 and MK-7 levels. The K requirement increased with age. They concluded that circulating vitamin K concentrations in elderly people should be kept higher than those in young people. Menaquinone plus vitamin D supplements reduced bone loss in another study.
Arterial calcification occurs with and without atherosclerosis. Higher vitamin K2 intake may reduce or prevent both disturbances of calcium metabolism. A study of 4500 elderly patients showed that a low dietary intake of K2 was associated with greater aortic calcification, myocardial infarction, and sudden cardiovascular death. A large study following 10,000 asymptomatic persons referred for electron beam tomography (EBT) screening and followed for 5 years for all-cause mortality showed that survival rates are associated with the amount of calcium present within the vasculature. Calcification was once believed to be an irreversible result of aging, contributing significantly to cardiovascular disease risk. However, it is now known that calcium accumulation is an actively regulated process involving vitamin K2-dependent MGP, the most potent inhibitor of calcification presently known. A fraction of MGP circulates in the bloodstream mirroring the tissue bound MGP. Carboxylated MGP in tissues binds calcium and inhibits deposition in the vessel walls. By binding calcium MGP contributes to removing it from the arteries, keeping them flexible. However, in order to perform its inhibitory function properly, MGP has to be activated by vitamin K2. In cases of vitamin K2 deficiency, MGP cannot prevent calcification properly, leading to increased risk of fatal cardiovascular events. A study of 4500 elderly patients showed that a low dietary intake of K2 was associated with greater aortic calcification, myocardial infarction, and sudden cardiovascular death. Bram et al gave 181 healthy, Caucasian postmenopausal women, daily supplement of 1 mg of phytonadione, plus 8 µg of vitamin D3, 500 mg of calcium, 150 mg of magnesium, and 10 mg of zinc. Loss of carotid artery elasticity was reduced only in the phytonadione group.
There is no evidence of toxicity from phytonadione or menaquinone (up to daily dose 45 mg). Schurgers and Vermeer suggested a µg phytonadione dosage of 1000 mcg daily. Braam et al used the same daily dose to inhibit the loss of carotid artery elasticity. However, several trials of osteoporotic, postmenopausal women have used menaquinone dosages as high as 45 mg per day.
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