Zinc Toxicity and PARP

Here's an article talking about the role that free zinc plays in increasing poly(ADP-ribose) polymerase activity and, as a result, apoptosis ("programmed cell death") of neurons:

http://www.ncbi.nlm.nih.gov/pubmed/15262265

Free zinc is really toxic and can cause all sorts of problems, and using zinc and copper in supplements is potentially really problematic. There's a lot of zinc in red meat or even other meats, and there's copper in legumes, etc. I'll try to post some of the links to articles, but there's a whole series of articles showing that high-dose zinc supplementation can produce neurodegeneration in people without pre-existing neurodegenerative disorders. Here are a couple, but there are many more:

http://www.ncbi.nlm.nih.gov/pubmed/12975299

http://www.ncbi.nlm.nih.gov/pubmed/15834043

http://www.ncbi.nlm.nih.gov/pubmed/10762525

I seriously doubt that those neurotoxic effects of excessive zinc are all due to copper depletion. The requirement for copper is really small and is something like 1 mg per day. There's a tendency to think of things in terms of zinc-induced copper depletion, but that's only one mechanism and is probably not the most important. Zinc can directly abolish the mitochondrial membrane potential, PARP is a zinc-finger protein that "uses" zinc for its functioning, and free zinc causes many effects that have nothing to do with copper depletion. Copper's required for S-adenosylhomocysteine hydrolase activity and also for complex IV activity ("cytochrome c oxidase"), but the requirement for copper is extremely low and can usually be obtained from foods. Any elevation of copper can cause wild damage to cells, also.

Here's an article showing that peroxynitrite contributes to neuronal apoptosis (and mentions that peroxynitrite can even cause cell death by necrosis) partly by liberating zinc from intracellular stores. The zinc then inhibits mitochondrial ATP production and helps lead to apoptosis:

http://www.ncbi.nlm.nih.gov/pubmed/14766175

In any case, as I've mentioned in previous posts, uric acid is probably the most potent, physiological peroxynitrite scavenger. It may actually "scavenge" peroxynitrite after the peroxynitrite has been converted into nitrosoperoxycarbonate, but that's a separate issue. Urate is not even really an antioxidant, in the sense that urate is actually degraded upon its nitrosylation/nitration by peroxynitrite and related molecules. I'll post a link to the series of reactions that degrade urate to allantoin, but the point is urate doesn't need to be regenerated, like other antioxidants. This is probably a major advantage, because most antioxidants have to be reduced, by the thioredoxin reductase enzyme system and other enzyme complexes, to keep exerting "antioxidant" effects. This requirement that they be regenerated is a potentially large limitation, given that regeneration always requires reducing equivalents (which in turn require adequate mitochondrial functioning, etc.). Urate/uric acid is more like a peroxynitrite "sink."