Different Perspectives on CoQ10 and Benzoquinones

I know there's a ton of research showing that CoQ10 is useful for treating cardiomyopathy and some neurological conditions or myopathies (here's a crude search that turned up 7,110 results: http://scholar.google.com/scholar?num=100&hl=en&lr=&q=%22coenzyme+Q10%22+cardiomyopathy+OR+heart+OR+Parkinson%27s+OR+neuroprotective+OR+Alzheimer%27s), and there's research showing it can slow the progression of Parkinson's disease. But before the CoQ10 craze of ever-increasing dosages, researchers used to use much lower doses to treat people with mitochondrial disorders [such as mtDNA mutations producing "complex I deficiency" (deficient activity of complex I), etc.]. Those were doses of non-Polysorbate-80-emulsified CoQ10, and now there are plans to use 2,400-3,000 mg (admittedly, the research is still mainly on the use of nonemulsified CoQ10) to slow the progression of Parkinson's? Here's an example:

http://www.ncbi.nlm.nih.gov/pubmed/15246848 (Shults et al., 2004)

I know that the Km('s) for the binding of ubiquinone to its binding sites on complex I and II is(are) substantially higher than the intramitochondrial or overall intracellular concentrations of endogenously-produced CoQ10, and that's one reason CoQ10 supplementation is rational. And using the more bioavailable forms, to maximize delivery to the brain to slow the progression of Parkinson's disease, would conceivably allow one to use lower overall dosages of CoQ10 than would otherwise be necessary, in the absence of an emulsified delivery form.

But there are significant disadvantages to the use of something so reactive to enhance mitochondrial activity, and enhancing complex I/II activity with CoQ10, especially in cells with compromised superoxide dismutase or catalase activities, as a result of damage or inflammation or whatever, isn't necessarily going to be beneficial. CoQ10, past a certain point or under certain conditions, could have significant "pro-oxidant effects." Enhancing complex I and II activity generates reactive oxygen species, of course, but there's research showing that, for example, the reduction potential, I think, of CoQ10 makes it more likely than similar compounds, like idebenone (another alternative electron acceptor and CoQ10 drug analogue that went through phase III trials, I think, in the treatment of Alzheimer's disease), to produce reactive oxygen species under anoxic/hypoxic conditions. And the need for CoQ10 to be regenerated by thioredoxin reductase is something that's cause for concern, particularly in view of the reactivity of benzoquinones.

And this potential for vitamin K activity, if it does occur at higher doses, is obviously worrisome. There are many reports in the literature of people having differing "sensitivities" to vitamin K, and that's one of the reasons managing the INR in people taking warfarin can be extremely difficult for doctors and patients:

http://www.ncbi.nlm.nih.gov/pubmed/14565795 (Kurnik et al., 2003)

There are many reports showing that benzoquinones can have vitamin K activity, and the antagonistic effect that CoQ10 can have on the anticoagulant effect of warfarin has not been adequately explained, from a mechanistic standpoint. Some of these are old articles, but these articles show differing results for the vitamin K activities of benzoquinones:

http://www.jbc.org/cgi/reprint/131/1/399 (Ansbacher et al., 1939) (pubmed misspells the author's last name)

http://www.jbc.org/cgi/reprint/235/4/1196 (Walter Wosilait, 1960)

http://www.ncbi.nlm.nih.gov/pubmed/14459956 (Kruse and Dam, 1962)

http://www.ncbi.nlm.nih.gov/pubmed/8948492 (Jacintha Ronden et al., 1996)

http://jpet.aspetjournals.org/cgi/content/abstract/147/1/130 (Lowenthal and Macfarlane, 1965) (pubmed: http://www.ncbi.nlm.nih.gov/pubmed/14255157?dopt=Abstract)

[Note: the article by Ronden et al. (1996) refers to CoQ10 and CoQ9 as prenylquinones, but this means they are prenylated benzoquinones.] I know the research is old, but, in the absence of research in many of these areas, one sometimes has to rely on reasoning. There may never be more systematically-done research on this type of issue. There is the one report, in the first article I linked to, that tocopherol quinone may have weak vitamin K activity (when it's supposed to always be a vitamin K antagonist), and CoQ10 is also supposed to always be a vitamin K antagonist (http://www.ncbi.nlm.nih.gov/pubmed/8948492). Those facts, together with the inconsistent results for the benzoquinones and the use of menadione (vitamin K3) to treat CoQ10-responsive mitochondrial disorders (http://brain.oxfordjournals.org/cgi/content/abstract/115/4/991-a and http://www.ncbi.nlm.nih.gov/pubmed/2128595 and many others) (the structures of vitamin K and CoQ10 compounds are very similar), suggest that very high hepatic concentrations of CoQ10 may produce low-level vitamin K activity. There may be minor metabolites that are only produced at very high dosages or that are produced as a result of the induction of cytochrome P-450 enzyme activities, by other medications that people are taking. That could explain the inconsistencies in the results for the benzoquinones, and the results are definitely not consistent. And the methodologies that supposedly rule out vitamin K activity for some of those benzoquinone compounds, in some of those articles, look suspect to me. You can't necessarily tell what's going on in a study that gives animals some arbitrarily-chosen dosage for a few days.

Some of the doses of CoQ10 that are being used in studies now, on humans, are enormous. And I realize that the concentration of CoQ10 in the heart is ten times the concentrations in other tissues, but the doses required to increase complex I and II activities, in extrahepatic tissues, are probably much lower than the doses that might have nonspecific "antioxidant" effects [or pro-oxidant effects or, as suggested by Brian Gage and Paul Milligan, 2005 (http://www.ncbi.nlm.nih.gov/pubmed/16043212), vitamin K activity].