I was probably too dismissive of some of these articles on thiamine, but I still think the lipid-soluble, thiamine prodrugs [benfotiamine, TTFD, and thiamine propyl disulfide (sulbutiamine)] have issues with them. For one thing, I think they could elevate thiamine levels excessively and disturb the transport of biotin, coenzyme A precursors (phosphopantetheine, pantothenate, etc.) or endogenously-produced lipoic acid (http://www.jbc.org/cgi/content/full/280/13/12422#REF37). There are some issues with the overlapping transport pathways of those sulfur-containing cofactors, meaning that no one knows how much biotin would interfere with thiamine or lipoic acid metabolism and transport. Biotin and thiamine transport may overlap to some extent: (http://www.ncbi.nlm.nih.gov/pubmed/16790503?dopt=Abstract). Pantothenic acid, lipoic acid, and biotin compete for transport into the brain, via the sodium-dependent multivitamin transporter (http://www.ncbi.nlm.nih.gov/pubmed/17645457). There are many more articles on those interactions for sulfur-containing cofactors/vitamins. The transport pathways seem to be fairly flexible and have redundancies, but high doses of any one of those cofactors could, in the long term, interfere with transport or metabolism of the others. Thiamine can also be transported by reduced folate carrier proteins (http://www.ncbi.nlm.nih.gov/pubmed/11997266?dopt=Abstract).
The main thing with thiamine is that dosages above a certain level are not going to produce any more benefits. There's this effect whereby an excess of thiamine can upregulate transketolase activity (the "transketolase effect" ), but I think doses of thiamine larger than about 200 mg/d are unlikely to produce further benefits. One of the reasons is that the pyruvate dehydrogenase (PDH) and alpha-ketoglutarate dehydrogenase (KGDH) multienzyme complexes are thought to be unusually sensitive to oxidative inactivation by superoxide and peroxynitrite, among other reactive species, such as in response to reperfusion (http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=15562436 pubmed (Erica Martin et al.): http://www.ncbi.nlm.nih.gov/pubmed/15562436). Providing extra thiamine can only enhance PDH and KGDH activities to a certain extent, especially in the presence of a lot of peroxynitrite and the like.
That's one reason things like uric acid interest me. Uric acid is the type of thing that could conceivably prevent some of the inactivation of the PDH and KGDH complexes, at least in endothelial cells. I need to read up on the extent to which uric acid is found or produced intracellularly. But peroxynitrite can also diffuse, and cross lipid bilayers, across two cell diameters (Radi et al.: http://www.ncbi.nlm.nih.gov/pubmed/11182518). This article (Matthias Hediger et al.) cites references that urate can be transported into vascular smooth muscle cells and endothelial cells (by the organic anion transporters, maybe): http://physiologyonline.physiology.org/cgi/content/full/20/2/125), but I think they're overstating these supposed toxic effects of it. They claim that urate interferes with endothelial cell proliferation, but at what concentration. This article shows that uric acid can limit lipid peroxidation and depletion of glutathione from the liver, suggesting an intracellular mode of action: (http://www.ncbi.nlm.nih.gov/pubmed/18501514). This article shows that acute increases in urate can "mobilize" endothelial progenitor cells, an effect that would be expected to be antiatherogenic, etc.: [http://jasn.asnjournals.org/cgi/content/full/18/5/1516 or pubmed (Daniel Patschan et al.): http://www.ncbi.nlm.nih.gov/pubmed/17409313?dopt=Abstract]. This article shows that administering uric acid, as an adjunct to the use of tissue plasminogen activator (tPA, the recombinant form of a thrombolytic protein) in treating ischemic stroke, improves the outcome and reduces lipid peroxidation in humans [pubmed (Amaro et al.): http://www.ncbi.nlm.nih.gov/pubmed/18271711]. But I'm sure there's a limit to the benefit from peroxynitrite scavenging, and I don't doubt that urate has allosteric or other regulatory effects on different proteins or enzymes, etc.
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