Vitamin K distribution in rat tissues: dietary phylloquinone is a source of tissue menaquinone-4

Abstract

The present study was undertaken to determine whether there is selective tissue distribution of vitamin K in the rat and whether this distribution mirrors the distribution of tissue vitamin K metabolism. The effects of feeding a vitamin K-free diet followed by resupplementation with phylloquinone (K1) were studied. K1was recovered in all tissues. In K1-supplemented rats, most tissues accumulated K1relative to plasma K1with the highest levels in liver, heart, bone, and cartilaginous tissue (sternum). Low K1levels were found in the brain. In the K1-free rats, relatively high K1levels were still found in heart, pancreas, bone and sternum. Surprisingly, menaquinone-4 (MK-4) was detected in all tissues, with low levels in plasma and liver, and much higher levels in pancreas, salivary gland and sternum. MK-4 levels exceeded K1levels in brain, pancreas, salivary gland and sternum. Supplementation with K1, orally and by intravenous infusion, caused MK-4 levels to rise. Some accumulation of K1and MK-4 in the mitochondrial fraction was found for kidney, pancreas and salivary gland. In the liver the higher menaquinones (MK-6–9) accumulated in the mitochondria. The results indicate that: (1) there is selective tissue distribution of K1and MK-4, (2) dietary K1is a source of MK-4. The results also suggest there may be an as yet unrecognized physiological function for vitamin K (MK-4).

Recent trends in the metabolism and cell biology of vitamin K with special reference to vitamin K cycling and MK-4 biosynthesis

“…Analysis of representative organs showed high concentrations of deuterium-labeled MK-4 in the cerebrum, and low concentrations in the liver in which the label was predominately found as K 1 . This is in agreement with the distribution of unlabeled compounds in previous studies (50)(51)(52). The authors also showed that rat intestinal IEC-6 cells were capable of removing the side chain of K 1 to generate menadione, which could be converted to MK-4.…”

“…Finally, Vkor Ϫ / Ϫ mice did show evidence of skeletal abnormalities characteristic of vitamin K defi ciency or VKA antagonism, which was obviously not prevented by VKORL1. It is worth mentioning that the relative expression of Vkorl1 mRNA was higher than for Vkor mRNA in brain, testis, and osteoblast-like cells ( 111 ), while previous data for MK-4 distribution shows that brain and bone (testis not measured) also have higher ratios of MK-4 to K 1 ( 51 ). Also, the lowest ratio by far of Vkorl1 to Vkor expression was found in the liver ( 111 ), which is also the organ with the lowest ratio of MK-4 to K 1 ( 51 ).…”

“…It is worth mentioning that the relative expression of Vkorl1 mRNA was higher than for Vkor mRNA in brain, testis, and osteoblast-like cells ( 111 ), while previous data for MK-4 distribution shows that brain and bone (testis not measured) also have higher ratios of MK-4 to K 1 ( 51 ). Also, the lowest ratio by far of Vkorl1 to Vkor expression was found in the liver ( 111 ), which is also the organ with the lowest ratio of MK-4 to K 1 ( 51 ). It might be worth investigating whether MK-4 is the favored substrate for VKORL1, although the relative in vitro affi nity data for K 1 >O and MK-4>O substrates does not support this ( 110 ).…”

“…In fact, the liver is the only organ or tissue in which the majority of vitamin K reserves comprise longchain forms, MK-7 through to MK-13, with only low concentrations of MK-4 ( 50 ). Extrahepatic tissues in rats ( 51,52 ) and humans ( 50 ) contain mainly K 1 and/or MK-4. In humans, K 1 concentrations comparable to the liver (10 pmol/g) are present in heart and pancreas, but low K 1 concentrations (<2 pmol/g) are present in brain, kidney, and lung ( 50 ).…”

Anti-Inflammatory Actions of Vitamin K

“…Research that started in the 1990s demonstrated that menadione was an important derivative from vitamin K1 that was converted in the rat to make the vitamin K2 congener menaquinone-4 [64][65][66][67]. The enzyme responsible for the conversion of menadione to menaquinone-4, UBIAD1 [68] has a wide distribution across species and likely plays a significant role in the vitamin K status of many animals (see chapter by O'Neil et al, this volume).…”