I thought I'd just mention the issue of copper intake again and just put a couple of basic articles up. I don't think zinc supplementation is a good idea, and copper supplementation is potentially really hazardous, too, except in tiny dosages (maybe 250-500 micrograms/d). The overall picture is that copper is required for iron export from cells (the "ferroxidase" activity comes from ceruloplasmin itself, I think), and iron can build up in astrocytes and cells in the bone marrow in copper deficiency. Copper is also required for complex IV activity (cytochrome c oxidase activity), superoxide dismutase, lysyl oxidase (required for collagen formation), lysyl oxidase related proteins (I forget the names) that are involved in axonal transport in some way, and I'm forgetting the rest of the copper-dependent enzymes. It also binds to S-adenosylhomocysteine hydrolase and does activate it, and copper is also required for dopamine beta-hydroxylase activity (the enzyme that converts dopamine into noradrenaline) and diamine oxidase activity (degrades histamine and polyamines, etc.). The locus ceruleus, the major noradrenergic cell group in the brain, appears slightly bluish (ceruleus, as in "cerulean blue," etc.; locus ceruleus translates crudely as "collection of blue points") under some circumstances, under the microscope, and it's apparently because of the copper bound to dopamine beta-hydroxylase (or possibly because of copper storage in neuromelanin pigments or because ceruloplasmin is more abundant and is transporting more copper into the cells).
Copper binds to specific residues (such as tyrosyl residues) on enzymes (at least in some cases it does) and nonenzymatically (or "autocatalytically") is incorporated into a protein tyrosyl quinone structure (topaquinone structures and tyrosyl quinone structures, formed when copper binds to tyrosyl residues on proteins). So there's no cofactor biosynthesis. It's autocatalytic/nonenzymatic, but the transport of copper to those enzymes, for incorporation into the tyrosyl quinones and topaquinones, is normally highly regulated and direct. Almost no intracellular copper is supposed to exist as free copper ions, but oxidative stress can cause metals, such as zinc and presumably copper, to be liberated en masse from storage sites (and thereby cause massive neurotoxicity, etc.). Peroxynitrite is a major species that does that, and it's one reason for my interest in uric acid as really the primary peroxynitrite scavenger/"sink" in humans.
Excessive zinc supplementation can cause copper deficiency and has been associated, in countless articles, with neurotoxicity and bone marrow toxicity (anemia, thrombocytopenia, pancytopenia). There's this assumption that all of the neurotoxicity and bone marrow toxicity is from zinc-induced copper depletion, but I don't think that's the case. Free zinc has a vast range of neurotoxic effects, and most of the effects have nothing to do with copper. Small amounts of copper are required for normal iron transport, normal mitochondrial activity, and collagen formation and axonal transport, and for SAHH and dopamine beta-hydroxylase activity, etc. But the point is that getting more than the RDA seems risky to me. There are case reports of people having grave bone marrow toxicity that appeared to be due to severe copper depletion, and I'm sure it does play a role in the zinc-induced toxic effects. But zinc could also cause bone marrow toxicity by all sorts of mechanisms that have nothing to do with copper. Here's one article that shows copper deficiency and zinc toxicity, but has the copper ever been shown to promote neurological recovery? (http://www.ncbi.nlm.nih.gov/pubmed/15834043?dopt=Abstract). I don't feel like looking for other articles. There's something about the wording or keyword choice in the articles on zinc toxicity. They don't come up on searches properly, and you need to try lots of different words like zinc+supplement+(thrombocytopenia OR cytopenias OR anemia OR pancytopenia OR "bone marrow" OR neurotoxicity OR neurodegeneration)...etc. There are tons of them, and I have lots that I've downloaded over the years and that are scattered around my computer.
There is reason to think that it might be wise, if one chooses to supplement with a miniscule dosage of copper, to use a chelated form. Copper oxide may not be absorbed well and at least does not have any appreciable bioavailability. The title of this article is "copper oxide should not be used as a supplement for either animals or humans": [Baker, 1999: (http://jn.nutrition.org/cgi/content/full/129/12/2278)]. Copper oxide is actually insoluble in water, I'm remembering, as I look at that article. Something like chelated copper (II) gluconate or copper as "amino acid chelate" is likely to have a reliable degree of bioavailability. I think supplement manufacturers are no longer allowed to put the word chelated or chelate on a supplement that does not, in fact, contain a chelated mineral. The difference between a chelate and a salt is the presence or absence, respectively, of coordinate covalent bonds. "Chelated copper gluconate" contains copper bound to one or more gluconate ligands by coordinate covalent bonds, but "copper gluconate" may be just copper ions and gluconic acid, in a crystalline form, that dissociate into ions in water. Chelates tend to be absorbed by dipeptide transporters or amino acid transporters in the intestinal tract.
I'd be willing to bet that chelated copper supplements are significantly more bioavailable and absorbable than copper from many foods, and that's one reason a 250-500 microgram (or less even, I suppose) dosage of a chelated copper supplement might be one approach. I don't know who decided on the dosages of copper in some supplements, but I'd just be willing to bet that chelated copper forms are quite a bit more potent than copper from food (making the high dosages that much more questionable). That might be equivalent to twice that amount from food. I don't know exactly, but the RDA is 900 micrograms to 1,200 micrograms of elemental copper per day (0.9-1.2 mg/d). I think copper is one of those cases in which the RDA people got it right. The articles on copper retention in humans show that it's pretty difficult to become copper deficient, but the articles don't and can't really show the adverse effects of copper. It's not likely to be possible to show, for example, that 2 mg/d is worse in some people and causes more intracellular free radical stress in the brain than 1 mg/d does. But given that a person is unlikely to become deficient from 1 mg/d, it seems like a better choice to me. This article also discusses the zero-bioavailability of copper oxide: (http://www.ajcn.org/cgi/reprint/67/5/1054S). If a person eats a lot of legumes or whatever, then...I don't know...the 250 mcg copper supplement may be unnecessary. The USDA copper content or nutrient content tables are available online and can give one a sense of the contents of minerals in foods. But the advantage of taking some tiny amount of a chelated form is that one wouldn't need to worry about poor bioavailability or insolubility or lack of dissociation from food constituents, etc. A lot of people, though, seem to have a problem with excessive amounts of copper in numerous disease states, and so it's probably absorbed fairly well. The main thing, though, is that the turnover of copper is very slow, and that's why I mention this type of detailed consideration about dosages or estimating one's intake. Zinc is abundant in meats, especially, and the USDA tables give one a sense of that. There's about 3-5 or more mg of zinc in single "servings" of meat, even though the USDA tables present the information in ways that are difficult to make sense of, sometimes.
Then there's always the tablet dissolution issues with some supplements, and those issues have been written about extensively. There are some independent "lab" organizations that have information online, testing dietary supplements, and it's always worthwhile to buy from a reputable manufacturer. Some of those independent laboratory sites have found tablets that can't be broken with hammers and would not dissolve at all. There's a lot of information about that type of thing in the literature, too. It's still, unfortunately, an issue in some cases.
If a person has a tendency toward copper overload or has any liver disease or inflammatory disease state, even low doses like 100-500 mcg could be hazardous. A person would want to talk with his or her doctor before taking something like copper, even in miniscule dosages, especially if there's any disease state or history of disease. I'm just putting this summary up, because the issue is so extraordinarily mind-bending and complex. The concept of the zinc/copper ratio of supplements is not valid, in my view. Zinc supplementation, for example, can upregulate metallothionein expression in various tissues, and that can then bind iron and copper. But in what way does it make sense to then increase the copper dosage to compensate? It doesn't make sense, but that's one way of looking at the zinc/copper ratio in supplementation. Additionally, it's not possible to evaluate copper status very easily. The serum copper or ceruloplasmin can tell a person that he or she is not deficient, but even those markers are not necessarily very telling. One can give people 30 mg of zinc in a study, but does the absence of a decrease in serum copper mean that zinc is safe or that copper is not accumulating, bound in an unstable way to metallothioneins, intracellularly in various tissues? No, and I've seen articles saying that basically the serum copper and ceruloplasmin are not very useful. One article used erythrocyte Cu/Zn-superoxide dismutase activity to evaluate copper status, but the tests for copper status are not very useful.
Another potential mechanism that could lead to erroneous conclusions in research is the way zinc can be collagenolytic and increase matrix metalloproteinase enzymes' activities, and copper can increase collagen formation. Copper is also required for clotting factor V and for factor VII (if memory serves), and zinc activates several different thrombolytic proteins. But the serum zinc is maintained quite effectively, and increasing one's zinc intake through food provides smaller amounts. Some of the adverse effects of copper could be explained by those potentially-prothrombotic effects, even though the research, unconvincing as it is, suggests that factor V levels decrease in response to copper supplementation or repletion (I'm sure that tiny amounts of copper are required for those clotting factors). But if the activity increases, where's the benefit from a decrease in the serum factor V protein content? But my point with the opposing effects on collagen and other processes, including the supposed "zinc-induced neurotoxicity as being due to copper depletion" and "zinc-induced bone marrow failure being due to copper depletion" is that zinc has effects that oppose copper's effects but that don't have anything to do with copper depletion. For example, zinc can inhibit heme biosynthesis by forming zinc(II) protoporphyrin, which is actually used as a marker for ineffective erythropoiesis or low-level anemia, in many articles. But that effect doesn't have anything to do with copper. And zinc can break down the extracellular matrix by activating matrix metalloproteinases, and copper might seem to be required in x amount to help "rebuild" the collagen or prevent some marker of collagenolytic activity from increasing in the blood. But if the zinc weren't being given in such high doses, the collagen breakdown might not be so high. So there's this tendency to attribute everything about excessive zinc supplementation to copper depletion, and that assumption is sort of built into the proposed zinc-to-copper ratios, in some cases. But the bone marrow toxicity might be due to zinc's bizarre effects of inhibiting mitochondrial activity directly, as has been shown in neuronal cells, etc. In many of those articles on zinc toxicity, the copper supplementation doesn't seem to work very well in treating the toxicities (bone marrow or neuronal/astrocytic/oligodendrocytic), especially for the neurotoxicity. Given the multitude of neurotoxic effects of zinc that have been identified in the context of research on Alzheimer's disease or other neurodegenerative diseases, it's reasonable to think that a lot of the neurotoxicity in those case reports had little to do with copper depletion.
Also, any decrease in serum albumin can seriously disturb zinc transport, and compensating for that with extra zinc is potentially an unsound strategy, for many reasons, in the extreme.
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