These are some more articles that discuss all of the mechanisms by which an excess of intracellular, free zinc can cause mitochondrial dysfunction and toxic effects on many other cellular processes. The authors of this article [Lemire et al., 2008: (http://oldwebsite.laurentian.ca/chem/vappanna/publications/J.%20Applied%20Toxicology%202008.pdf)(http://www.ncbi.nlm.nih.gov/pubmed/17582580)] discuss the fact that an excess of zinc can inhibit various TCA cycle enzymes, such as aconitase, and other mitochondrial enzymes. Although the authors note that zinc can interfere in a generalized way with enzymes and proteins that contain iron-sulfur clusters, aconitase is known to also utilize nonheme iron (I mean nonheme iron that is also non-iron-sulfur-cluster-bound iron) [see, for example, Lee et al., 1996: (http://scholar.google.com/scholar?num=100&hl=en&lr=&q=aconitase+nonheme+iron)]. Zinc can be utilized to form zinc protoporphyrin, and I wonder if zinc isn't actually incorporated into iron-sulfur clusters. But it wouldn't have to be, and zinc could reasonably be expected to displace, with particular ease, nonheme iron (i.e. Fe2+/Fe3+) from its binding sites on enzymes whose catalytic activities or regulatory functions depend on the presence of bound, nonheme iron.
I think neurotoxicity from excessive zinc supplementation is a very serious issue, and, in my opinion, low-level, pathological changes, such as psychiatric symptoms or gradually-progressing neurotoxicity, may result from dosages of zinc that many people would not view as being especially massive. Only a relatively few authors, as far as I can tell, have written articles, over the last few decades, discussing the potential hazards of zinc supplementation at the more commonly-used dosages. Even fewer articles on the nutritional aspects of zinc have considered that problems with zinc supplementation may have nothing to do with copper depletion, even when copper is depleted as a result of the excess zinc. In my opinion, based on the literature, many of the cases of neurotoxicity associated with excessive zinc supplementation (there are many, many case reports in the literature, and I don't feel like listing dozens of them out, right now, in this posting) may have had relatively little to do with copper depletion, and one sees that copper supplementation, in many cases, did not very effectively ameliorate the neurological disorders and demyelination that researchers had found in association with excessive intakes of zinc. [Some of the articles and case reports are scattered throughout the results of this search: (http://scholar.google.com/scholar?num=100&hl=en&lr=&q=%22zinc+supplementation%22+neurotoxic+OR+neurological+OR+demyelinating+OR+demyelination+OR+%22white+matter%22), and this is an "instructive-but-not-comprehensive" list of articles that google scholar classifies as being related to an article on excessive zinc supplementation: (http://scholar.google.com/scholar?num=100&hl=en&lr=&q=related:-bvm-ASLfasJ:scholar.google.com/)]. In most cases, the researchers have discontinued the zinc supplementation at the same times they have initiated copper supplementation, and then the researchers have attributed the modest improvements in the neurological conditions or anemia or thrombocytopenia or pancytopenia to the copper repletion. In reality, the absence of zinc may have been the primary and more important factor that led to the improvements.
I've discussed, in past postings, the extraordinarily complex aspects of zinc metabolism and homeostasis, and another issue is that serum copper and ceruloplasmin are not sensitive or very reliable indicators, in my opinion, of the intracellular copper concentrations or of copper status in people who are not grossly copper-deficient. Serum zinc is also not thought to be a reliable measure of zinc status [Fung et al., 2002: (http://www.ncbi.nlm.nih.gov/pubmed/16215013)], and Fung et al. (2002) found that, even in people who had evidently been deficient in zinc and who had appeared to respond favorably to zinc supplementation, zinc supplementation did not increase serum zinc. These are major obstacles to nutritional research on zinc, in my opinion, and I would seriously question the validities of many descriptions, in the literature, of "zinc deficiency." Here's an article whose author discusses the potential neurotoxicity of zinc supplementation [Levenson, 2005: (http://www.ncbi.nlm.nih.gov/pubmed/15869126)], and here's a remarkable article, from 1989, in which Fosmire (1989) [Fosmire, 1989: (http://journals.lww.com/nutritiontodayonline/pages/articleviewer.aspx?year=1989&issue=05000&article=00005&type=abstract)] displayed remarkable prescience and subjective insight in relation to the potential problems that, in my opinion, could develop with dosages of zinc that many people would not view as being "excessive." I don't think zinc supplementation is a good idea in most cases, but that's just my opinion. I also don't think copper supplementation, above some tiny dosage (such as ~250-500 micrograms of elemental copper, to reach the RDA in combination with one's specific dietary intake), is a good idea, in many cases, but that's also just my opinion. A person would obviously want to discuss these issues with his or her doctor, given that one's unique, individualized nutritional needs are of paramount importance. I also think that the use of supplemental copper to compensate for the copper-depleting effects of zinc supplementation does not make sense and generally just has the potential to cause copper toxicity, but these are just my opinions.
I know this is a disturbing topic, but there's a kind of insanity in the way the different branches of research on zinc remain separated from one another. There's a vast amount of research showing copper-independent neurotoxic effects and extraordinarily complex, dynamic mechanisms of neurotoxicity from excesses of free zinc (http://scholar.google.com/scholar?num=100&hl=en&lr=&q=zinc+neurotoxicity), and then there's the nutritional research on zinc. People seem to think that zinc-induced neurotoxicity is an all-or-nothing phenomenon. The assumption is that high dosages, such as are discussed in the case reports of neurotoxicity or demyelination, can cause problems but that the absence of overt neurological symptoms, in people taking lower doses, is in some way evidence that those lower dosages are not producing any pathological effects in the brain and spinal cord. It makes no sense to me to think that there would be no potential for problems in response to some of these lower dosage ranges, but that's just my opinion. The main reason I think that is that a multitude of factors can influence the amounts of zinc that are being released from intracellular binding sites, and I would expect that both the amounts of intracellular free zinc in neurons and the consequences of that zinc could be drastically different among different individuals with similar serum zinc levels and zinc intakes. The authors of this article discuss the possibility that the therapeutic intake range for zinc may well be small [Maret and Sandstead, 2006: (http://www.ncbi.nlm.nih.gov/pubmed/16632171)], and it's time to face some of these issues, which I feel are serious, relating to zinc and copper supplementation.
No comments:
Post a Comment