Proper Cu+ and Zn2+ absorption
2021 update: This post has been password protected since it was created May 19th 2020. You may not determine whether or not copper is safe for you or a senior you love by reading this post. You are cordially invited to take this information to your physician and have a discussion with them as to whether Cu+ is safe based on the peer reviewed science presented in this post.
Some health care providers have expressed concern that copper in the diet may interfere with zinc absorption. Based on a recent Maares and Haase (2020) review, it is hard to conceive how Cu+ could interfere with Zn2+ absorption by Zip4 in the apical membrane and excretion from the enterocyte into the blood by ZnTn-1. Perhaps what Mitosynergy calls toxic copper, Cu2+ , could conceivably interfere with Zn2+ absorption. Doguer (2018) and Maares and Haase (2020) mention the possibility of Zn2+ and Cu2+ entering the enterocyte by way of a divalent metal ion transporter. Doguer (2018) has labeled the reductase in proximity to Ctr1 as a brush-border membrane (BBM) ferric iron reductase duodenal cytochrome B (DCYTB) that can reduce +3 iron and +2 copper. These include the major iron importer divalent metal-ion transporter 1 (DMT1).
Clinicians might also enjoy a Nishitio and Kambe (2018) review on copper, zinc, and iron.absorption from the gut. Whether DCYTB is a Cu2+ reductase for Ctr1 seems to remain a question. One could argue that the Mitosynergy’s Cu(I)NA2 is a specially formulated copper supplement that does not require this reductase.
Copper and Immune Function
- Copper and the immune system started out with an examination of the role of the neutrophil to lymphocyte ratio that was reported to be out of whack in severe COVID-19 infections. Don’t we need neutrophils as part of our innate immune system? Peer reviewed literature was reviewed on the impact of copper deficiency on the innate and antibody producing adaptive immune system.
- Fish and Human Studies is a presentation of data on Cu(I)NA2 on neutrophil and lymphocyte counts in fish and humans. improves antibody production against a fish pathogen in the fish studies. Some thoughts on the role of Cu(I)NA2 in beefing up the mitochondria in antibody producing plasma cells are presented.
- Copper and the renin agiotensin system Hypertension is a risk factor for severe COVID-19 infections. This virus binds to the angiotensin converting enzyme 2 (ACE2) cell surface enzyme. ACE2 is part of the renin-angiotensin-system (RAS) that our body uses to maintain blood pressure. It is activated by circulatory collapse that may occur in bacterial and fungal infections. Activation of the RAS is often associated with super oxide, a reactive oxygen species, production. I looked at literature showing that angiotensin II may up regulate the expression of Cu/Zn superoxided dismuatase 3.
Proper Copper and the Copper-2 Hypothesis
Dr George Brewer is a professor of Human Genetics at the University of Michigan. Dr Brewer became interested in the link between Alzheimer’s Disease and copper in the +2 oxidation state from water pipes in his studies of Wilson’s Disease. Wilson’s Disease patients have a defect in the copper export protein ATP7B that prevents them from eliminating excess copper in the bile, and ultimately the feces. Dr. was investigating tap water from sites across the United States. He found that tap water from many locals had Cu2+ exceeding concentrations found to exacerbate progression of Alzheimer’s Disease in animal models. Dr Brewer is hypothesizing that Cu2+ does not cause Alzheimer’s Disease but rather enables the epidemic (Brewer 2019). Dr Brewer also suggested that Cu2+ found in most dietary supplements could hasten the progression of Alzheimer’s Disease. The historical increase in meat consumption was down played as source of increased dietary copper. Dr Brewer hinted at the importance of two pools of blood borne copper: (1) bound to ceruloplasmin and (2) “freely” bound to blood proteins like albumin.
Dr Marc Solioz of Marc Solioz Department Clinical Research, University of Bern, dismisses the Copper-2 hypothesis. The United State and Switzerland have about the same incidence of Alzheimer’s Disease even though the U.S population consumes more red meat, takes more supplements, and is more likely to have copper pipes. Switzerland is unique in that copper water pipes were never used.
Ceruloplasmin bound copper and free copper
Techio and others (2016) of the BioMarkers Laboratory of Brescia, Italy found that non-ceruloplasmin bound plasma copper correlated with Alzheimer’s Disease brain abnormalities compared with ceruloplasmin bound copper. Squitti and coworkres (2014) followed patients with mild cognitive impairment (MCI) to test the hypothesis that non-ceruloplasmin bound copper is a risk factor for progression to ALzheimer’s Disease. They concluded that their results might warrant dietary intervention to lower the risks. Park and coworkers (2013) found elevated copper and ceruloplasmin in Korean Alzheimer’s Disease patients. An inverse relationship was found between cognitive performance and serum copper. These authors also speculated that Alzheimer’s Disease patients may have defective (apo) ceruloplasmin that lacks the copper cofactor. Wang and Wang (2019) in their review argue that properly functioning ceruloplasmin is neuroprotective.
A note of skepticism
George Brewer and others make a very compelling argument for Cu(II) being toxic copper. According to conventional wisdom reviewed by Doguer (2018) Cu+ is secreted directly into the portal circulation where it is picked up by the liver for packaging into ceruloplasmin. Surely Cu+ would not remain in the +1 oxidation state in this unchaperoned mode. Most models have the Menkes ATPase (ATP7A) directly secreting Cu+ into the blood.
- Are the oxygen tensions in the portal vein low enough to preserve the +1 oxidation state long enough to get to the liver?
- ATP7A loads SOD3 in the Golgi. Is there any indication of regulated release of Cu+ to apo copper binding proteins in the serum? An abstract from a Russian language publication (Tsymbalenko 2000) synthesized peptides corresponding to two of the four extracellular loops of ATP7A. One of these peptides was able to bind to a domain of the blood copper transport protein ceruloplamin.
The following was obtained from the UniProt.org database.
The manner in which the COVID-19 has hit nursing homes and the elderly hard has lead Mitosynergy to reexamine old data on Cu(I)NA2 and immune function. We also have to reexamine the “copper-2 hypothesis” regarding dietary copper and general fear that copper in any oxidation state potentiates Alzheimer’s Disease. The general consensus is that ceruloplasmin bound copper is okay and it is the “free” copper bound non specifically to serum proteins that is an Alzheimer’s Disease risk factor. We can propose a mechanism by which dietary Cu+ is more likely to end up ceruloplasmin bound than Cu2+ , but we have no proof as of this writing. Given the proven role of copper in immune function, a Cu+ supplement may be prudent as long as the elderly patient’s blood is tested for “free” and ceruloplasmin bound copper.
2021 update: It would seem that most, if not all, residents of nursing homes have been vaccinated for Covid-19. Hopefully the medical staff of nursing homes will find information presented in this post useful in evaluating whether copper supplementation would be helpful for their residents.
Brewer GJ. (2019) Avoiding Alzheimer’s disease: The important causative role of divalent copper ingestion. Exp Biol Med (Maywood). 244(2):114-119. Link
Doguer C, Ha JH, Collins JF. (2018) Intersection of Iron and Copper Metabolism in the Mammalian Intestine and Liver. Compr Physiol. 8(4):1433-1461. Link
Maares M, Haase H. (2020) A Guide to Human Zinc Absorption: General Overview and Recent Advances of In Vitro Intestinal Models. Nutrients. 2020 Mar 13;12(3). pii: E762. Link
Nishito Y, Kambe T.(2018) Absorption Mechanisms of Iron, Copper, and Zinc: An Overview.J Nutr Sci Vitaminol (Tokyo). 64(1):1-7. Link
Park JH, Lee DW, Park KS. ( Elevated serum copper and ceruloplasmin levels in Alzheimer’s disease. Asia Pac Psychiatry. 6(1):38-45.
Solioz M. (2020) Low copper-2 intake in Switzerland does not result in lower incidence of Alzheimer’s disease and contradicts the Copper-2 Hypothesis. Exp Biol Med (Maywood). 245(3):177-179. Link
Squitti R, Ghidoni R, Siotto M, Ventriglia M, Benussi L, Paterlini A, Magri M, Binetti G et al (2014) Value of serum nonceruloplasmin copper for prediction of mild cognitive impairment conversion to Alzheimer disease. Ann Neurol 75(4):574–580. Link
Tecchio F, Vecchio F, Ventriglia M, Porcaro C, Miraglia F, Siotto M, Rossini PM, Rongioletti M, Squitti R. (2016) Non-Ceruloplasmin Copper Distinguishes A Distinct Subtype of Alzheimer’s Disease: A Study of EEG-Derived Brain Activity. Curr Alzheimer Res.13(12):1374-1384.
Telianidis J, Hung YH, Materia S, Fontaine SL.(2013) Role of the P-Type ATPases, ATP7A and ATP7B in brain copper homeostasis. Front Aging Neurosci. 2013 Aug 23;5:44. Link
Tsymbalenko NV, Platonova NA, Puchkova LV, Mokshina SV, Sasina LK, Skvortsova NN, Mishchenko BS, Egorov TsA, Gaĭtskoki VS. (2000)[Identification of a fragment of ceruloplasmin, interacting with copper-transporting Menkes ATPase].[Article in Russian] Bioorg Khim. 2000 Aug;26(8):579-86.
Wang B Wang X-P (2019) Does Ceruloplasmin Defend Against Neurodegenerative Diseases? Curr Neuropharmacol. 17(6): 539–549. Link