Tissue-specific utilization of menaquinone-4 results in the prevention of arterial calcification in warfarin-treated rats.

The effects of vitamin K (phylloquinone: K1 and menaquinone-4: MK-4) on vascular calcification and their utilization in the arterial vessel wall were compared in the warfarin-treated rat model for arterial calcification. Warfarin-treated rats were fed diets containing K1, MK-4, or both. Both K1 and MK-4 are cofactors for the endoplasmic reticulum enzyme gamma-glutamyl carboxylase but have a structurally different aliphatic side chain. Despite their similar in vitro cofactor activity we show that MK-4 and not K1 inhibits warfarin-induced arterial calcification. The total hepatic K1 accumulation was threefold higher than that of MK-4, whereas aortic MK-4 was three times that of K1. The utilization of K1 and MK-4 in various tissues was estimated by calculating the ratios between accumulated quinone and epoxide species. K1 and MK-4 were both equally utilized in the liver, but the aorta showed a more efficient utilization of MK-4. Therefore, the observed differences between K1 and MK-4 with respect to inhibition of arterial calcification may be explained by both differences in their tissue bioavailability and cofactor utilization in the reductase/carboxylase reaction. An alternative explanation may come from an as yet hypothetical function of the geranylgeranyl side chain of MK-4, which is a structural analogue of geranylgeranyl pyrophosphate and could interfere with a critical step in the mevalonate pathway.

Menaquinone-4 in breast milk is derived from dietary phylloquinone.

The effect of maternal phylloquinone supplementation on vitamin K in breast milk was studied to establish: (1) if phylloquinone is the source of menaquinone-4 in breast milk; (2) the dose-effect relationship between intake and obtainable levels. Four groups of lactating mothers with a full-term healthy infant participated and took oral phylloquinone supplements of 0.0 (n 8), 0.8 (n 8), 2.0 (n 8), and 4.0 (n 7) mg/d for 12d, starting at day 4 post-partum. Milk samples were collected on days 4, 8, 16, and 19. Blood samples were collected on days 4 and 16. Vitamin K and vitamin E concentrations, the latter for reason of comparison, were assayed. Phylloquinone and menaquinone-4 were present in all milk samples: 5.84 (SD 2.31) and 2.98 (SD 1.51) nmol/l (n 31) respectively, in colostrum (day 4 sample). A strong correlation between the vitamers was found (r 0.78, P<0.001). Breast-milk phylloquinone levels were raised in a dose-dependent manner: 4-, 12-, and 30-fold on day 16 for the 08, 2.0, and 4.0 mg group respectively. In addition, menaquinone-4 levels were higher: 2.5- (P<0.05) and 7-fold (P<0.001) in the 2.0 and 4.0 mg groups respectively. Plasma of supplemented subjects contained 3-, 5-, and 10-fold higher phylloquinone levels on day 16. Detectable menaquinone-4 was found in ten of thirty-one day 4 plasma samples. All day 16 plasma samples of the 4mg supplemented group contained the vitamin. There was no correlation between the K-vitamers in plasma. Vitamin E and phylloquinone appear to differ in their distribution in breast milk, milk:plasma concentration ratios were < or =1 and 3-5 for vitamin E and phylloquinone respectively. The milk:plasma concentration ratio of menaquinone-4 was >10. In conclusion, dietary phylloquinone is a source of menaquinone-4 in breast milk. Phylloquinone supplementation to lactating mothers may be of benefit to the newborn infant, since both phylloquinone and menaquinone-4 are raised by supplementation.