Vitamin K Activity and CoQ10: Concerns and Complexity Upon Complexity

In this article (Brian Gage and Paul Milligan, 2005), the authors suggest the possibility that coenzyme Q10 (CoQ10/CoQ-10) may have vitamin K activity (meaning that it could substitute for vitamin K in the vitamin K cycle and potentially increase levels of clotting factors):

http://www.ncbi.nlm.nih.gov/pubmed/16043212

The implications of this suggestion are really significant and somewhat disturbing. I'll collect some of the links, later today, to articles that lend credence to their hypothesis (one line of evidence is that menadione, a form of vitamin K, has been used as an "alternative electron carrier" in the treatment of mitochondrial disorders, and the idea is that it binds to complex I and complex II and substitutes for CoQ10), even though the effect would probably occur mainly at some of the extremely high doses of CoQ10 (and ubiquinol, or CoQH2, the reduced form of CoQ10) that are being used in trials to slow the progression of Parkinson's disease or produce other effects.

Even though some articles show vitamin K antagonism by CoQ10 and, similarly, tocopheryl-quinone (a vitamin E metabolite at very low levels), one obscure article shows vitamin K activity for tocopheryl-quinone (tocopherol quinone). That metabolite of vitamin E is a benzoquinone, and multiple articles have shown vitamin K activity for benzoquinones. This is the type of article that shows the extreme complexity of the enzymes of the vitamin K cycle. Managing the issues relating to dietary vitamin K intake and warfarin dosages can be extremely complicated for doctors, and there are still many unanswered questions about the influence of vitamin K on clotting factor production. Here's the article, in which the authors discuss the way an excess of vitamin K, or a benzoquinone with vitamin K activity, could access or bind to an enzyme of the vitamin K cycle in an "atypical" manner or at an alternate site on the enzyme [implying that there could be strange concentration-dependences for the effects of benzoquinones, particularly in terms of the ratio of the concentrations of the benzoquinone and the antagonist (such as warfarin)]:

http://jpet.aspetjournals.org/cgi/content/abstract/157/3/672
(pubmed: http://www.ncbi.nlm.nih.gov/pubmed/6048023?dopt=Abstract)

If CoQ10 has vitamin K activity--and it may at high levels--the effect would be relatively weak in comparison to vitamin K itself. But with the enormous dosages and high-bioavailability, self-emulsifying delivery systems that have been developed to enhance CoQ10 bioavailability, the amounts of CoQ10 that are not bound to sites on the electron transport chain could become very significant. The bioavailability of self-emulsifying ubiquinol is just almost absurdly high, and one study showed a relatively low dose can increase plasma ubiquinol 11-fold. Even if CoQ10 has 1/5000th of the vitamin K activity that vitamin K has, it's conceivable that, at high doses, a high intracellular concentration could influence coagulation parameters.

I know the standard explanation is that CoQ10 increases warfarin clearance by enhancing the cytochrome P-450-mediated metabolism of warfarin (the idea, as I understand it, is that CoQ10 could enhance all cytochrome P-450-mediated reactions, by enhancing complex I and complex II activities). But the dosage forms of CoQ10 that are being sold have become just really large and keep increasing. Self-emulsifying forms of CoQH2 are being sold now, and those could have something like 6 times the bioavailability of some nonemulsified CoQ10 [the main emulsifiers, as far as I know, that produce these strong self-emulsification effects are Tween-80 and Tween-60 (polysorbate-80 and polysorbate-60)]. I remember reading that oil-in-water microemulsions, or something near to them, can be created by mechanical mixing, without sonication, of Tween-80, in combination with something like a medium-chain-triglyceride cosurfactant, and lipids of low water-solubility.

I also think it's important to remember that CoQ10 is a benzoquinone. I almost shouldn't have to say any more than that. If one wants to see what I'm getting at, do some searches on benzoquinone and...I don't know. N-acetyl-para-benzoquinoneimine (NAPQI) is a benzoquinone. I know that compound can act as a hapten and is much more reactive than ubiquinone, and I know CoQ10 is biosynthesized and is in every cell. But CoQ10 is not normally found at enormous intracellular concentrations. CoQ10 also has to be regenerated (reduced, from ubiquinone into ubiquinol, essentially) by the cytosolic thioredoxin reductase enzyme system (Ling Xia et al., 2003: http://www.jbc.org/cgi/content/full/278/4/2141 pubmed: http://www.ncbi.nlm.nih.gov/pubmed/12435734?dopt=Abstract). I just mean that that system does not have an unlimited capacity to deal with overwhelming concentrations of benzoquinones, and quinones are just very reactive compounds.

Even aside from the vitamin K issue (but also with reference to it, given that metabolites of CoQ10 would be benzoquinone derivatives), it's conceivable that minor, peroxisomal or microsomal cytochrome P-450-derived metabolites of CoQ10 could start to appear, as the intracellular CoQ10+CoQH2 concentrations are drastically increased.

The main message, though, has to do with vitamin K itself. Even though there are some sites on the internet that would have people believe taking vitamin K supplements will be helpful for "bone health" or for preventing aortic calcification, the much more likely outcome would be an increase in thrombogenicity. Even in the literature, there's a misconception that increasing one's vitamin K intake will not increase clotting factor levels, but this is not true. Taking vitamin K supplements is potentially disastrous, particularly in anyone with a thrombogenic condition or blood vessel disease, and the prothrombin levels have been shown to increase in proportion to the intake. The vitamin K levels in food are relatively low, and the vitamin K from foods (even from those with high levels of vitamin K (spinach, etc.)) is not absorbed as efficiently as vitamin K from supplements. Only tiny amounts of vitamin K are required for clotting factor production.

Vitamin K is being sold in enormous dosage forms, and any reduction in aortic calcification (some proteins that are post-translationally gamma-carboxylated, in a vitamin K-dependent manner, can act as calcium-binding proteins and sometimes prevent soft tissue calcification) would, in my opinion, be likely to be overshadowed, in a potentially catastrophic manner, by an increase in vitamin K-dependent thrombogenicity.