**4. Concluding remarks**

the regulation of intracellular NADPH, may indicate another important feature of the anti-

Vitamin K1 and K2s are broken down in the liver, and this is the only organ that has been reported to be responsible for the catabolism of these vitamins [73]. Early metabolism studies in men using radioactive vitamin K1 has revealed the catabolites to be side-chain shortened carboxylic acid products, the more abundant being a 5-carbon aliphatic acid, while the less abundant is a 7-carbon aliphatic acid containing a single double bond (**Figure 2**) [74]. These compounds are glucuronidated in the liver for excretion in the bile or through the kidneys. In human studies, the level of the catabolites varies with the amount of vitamin K ingested at pharmacological doses, as either phylloquinone or menaquinone-4 [75] or with dietary

We have found that both of these acid catabolites cannot participate in the gamma-carboxylation reaction and are, in fact, inhibitors or the vitamin K gamma-carboxylase enzyme (Soper

**Figure 2.** The metabolism of vitamin K1 (A) and vitamins K2 (B) with the common generation is the 7-carbon carboxylic acid catabolite, NaQuinate (C), which is further broken down to the 5-carbon carboxylic acid catabolite (D).

Our recent studies with the 7-carbon carboxylic acid catabolite of vitamin K, NaQuinate (**Figure 1**), found significant attenuation of LPS-challenged osteoblast-like MG63 cell IL-6 release [77]. This has likely *in vivo* implications, as in humans NaQuinate is usually present at high levels following pharmacological vitamin K dosing, irrespective of the source of vitamin K as either vitamin K1 or any of the vitamin K2 vitamers (**Figure 2**) [75]. Parallel experiments in MG63 cells using 1,25-(OH)2-vitamin D3 or interleukin-1β as agonists showed similar suppression of IL-6 release by NaQuinate (Soper and Hodges, unpublished data). Interestingly, LPS-challenged MG63 cells were substantially less affected by the 5-carbon carboxylic acid vitamin K catabolite (**Figure 2**), which only differs from NaQuinate by 2 carbon atoms and a

These results are in agreement with our earlier findings with LPS-challenged primary human fibroblast cultures [56]. Furthermore, if the carboxylic acid function on the catabolites is blocked with a methyl group, the LPS-induced release of IL-6 is greatly reduced in MG63 cells

inflammatory character of menadione.

160 Vitamin K2 - Vital for Health and Wellbeing

phylloquinone intake [76].

and Hodges, unpublished data).

carbon-carbon double bond [77].

*3.2.2. Inhibition of inflammation by a vitamin K catabolite, NaQuinate*

Vitamin K has been found to have anti-inflammatory activity in an increasing number of studies. This inhibitory activity would appear to be directed through inhibition of NF-κB signalling. In cell culture experiments, it is often mentioned that the cells needed to be primed with vitamin K before being challenged with agonists. Furthermore, experimental results are immerging that show inhibition of cytokine release in agonist-challenged cell culture and animal models, which in the light of vitamin K deficiency in chronic diseases, may reflect on a vitamin K role in organ homeostasis. Therefore, the defining vitamin K sufficiency on the basis solely of adequate functional blood clotting factors is likely to be an over-simplification and needs to be considered more fully.

The question is open as to the value of vitamin K in a therapeutic or a prophylactic role. For example, a vitamin K deficient, seriously ill patient is unlikely to benefit greatly from a vitamin K intervention, but a patient with a chronic inflammatory disease may. This can only be highlighted in large community studies, which need to be run over many years in large numbers of volunteers.

However, there are already some indications of prophylactic benefit of increased vitamin K intake in large population studies in Japan. Exploring consumption of 'natto', a live menaquinone-7 producing bacteria (*Bacillus subtilis* subsp) culture food product from fermented soybean that is culturally more favoured in the east than the west of Japan found that ingestion substantially increases human circulating menaquinone-7 levels and that bacterial gut colonization was evident several days after a single 80 g natto portion [78]. Intriguingly, prefectural sales of natto also linked consumption with a notable decrease in age-related hip fractures in eastern Japanese population [78].

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Given the safety of vitamin K, even in high pharmaceutical doses, supplementation may have a benefit, beyond meeting coagulation demands than is generally perceived, particularly in early chronic inflammatory diseases and inflammaging.
