Magnesium Citrate and Ceruloplasmin

Prepared for Natural Vitality by the Think Healthy Group in Collaboration with the Center for Magnesium Education & Research, LLC. Republished here with the permission of Dr. Rosanoff.

Facts About Ceruloplasmin

• Ceruloplasmin is the major copper-carrying protein in the blood and plays an active role in the metabolism of iron.
• Ceruloplasmin binds free copper and iron thus inhibits their ability to start free radical information.
• There is a theory that the free copper and iron-binding activity of ceruloplasmin decreases lipidoxidation (i.e., is an antioxidant) and the development of atherosclerosis (based on cell studies). Human studies have not confirmed this theory.

Citrate and Ceruloplasmin

• It is well known that adequate magnesium status conveys antioxidant capability to a human body.
• Most studies on citrate and ceruloplasmin are over 25 years old and out of date. Many are from the 1960s.
• One 8-ounce glass of orange juice contains about the same amount of citrate as one serving (2 tsp) of Natural Vitality’s Natural Calm.

Some cell and animal studies suggest that either citrate or ascorbic acid can inhibit the activity of ceruloplasmin. For example, Lovstad (1996) suggested that 10-mM concentrations of citrate can inhibit the ferroxidase activity of ceruloplasmin in a cell study.

There are three problems with cell and/or animal studies such as Lovstad (1996):

1. Normal human plasma concentrations of citrate range between 0.05 mM and 0.3 mM.
2. 10-mM plasma concentrations (30 to 200 times normal) are likely only achieved through intravenous administration of citrate for medical purposes and not through a typical recommended dose of a magnesium citrate supplement.
3. Humans and other mammals filter and excrete citrate much more efficiently than rats and other test animals.Human intervention studies have not been able to reproduce these findings reported in cells and/or animals.To theoretically inhibit the activity of ceruloplasmin, a human would need to consume levels of either citrate and/or vitamin C (ascorbic acid) that are not possible through food intake. One would need to consume at least an entire 8-ounce container (56 servings) of Natural Vitality’s Natural Calm magnesium citrate supplement in one serving to get this effect.

Doctors have been using high-dose vitamin C for decades without any difficulties.

There is no credible scientific evidence that taking magnesium citrate at levels recommended on supplement labels has any effect on ceruloplasmin.

Overview: The Effect of Magnesium Citrate on Ceruloplasmin

Scope of Work

The Center for Magnesium Education and Research is providing this scientific mini-review of how magnesium citrate affects ceruloplasmin based on the current peer-reviewed scientific literature to date. Consumer education on how magnesium citrate affects ceruloplasmin was developed based on the mini-review of the scientific literature.

Methodology

PubMed Search 1: (magnesium[Title/Abstract]) AND ceruloplasmin[Title/Abstract]

PubMed Search 2: (citrate[Title/Abstract]) AND ceruloplasmin[Title/Abstract]

Exclusion criteria: non-English studies

64 articles were identified and their abstracts were reviewed. 13 articles were identified as relevant and were reviewed in full-text.

Results and Conclusions

Ceruloplasmin is the major copper-carrying protein in the blood and plays an active role in the metabolism of iron. Lower ceruloplasmin levels may indicate either a copper and/or zinc deficiency or a vitamin C overload (using amounts far greater than typical human consumption). Ceruloplasmin has been proposed as an important factor in cellular iron efflux and has been suggested to be downregulated in atherosclerotic plaques.³ Ceruloplasmin functions as an antioxidant. Free copper and iron are powerful catalysts of free radical damage. Ceruloplasmin binds free copper ions and prevents free radical–induced oxidative damage.⁴ In a similar manner, ceruloplasmin facilitates iron loading onto its transport protein (i.e., transferrin) and prevents free ferrous (Fe+2) from participating in free radical–generating reactions.⁴

The interaction of copper and ascorbate (i.e., vitamin C) has been described since the early 1960s. Dietary ascorbate has been suggested to interfere with copper absorption in several animal and human studies at high levels.⁵ Since ascorbate seems to influence the free metal, and since 90–95% of copper found in the serum is bound to ceruloplasmin, some scientists have hypothesized that ascorbate (or citrate) may have an influence on this protein. The oxidase activity (i.e., the ability to bind free copper and iron) of ceruloplasmin has been suggested to be lower in the presence of ascorbate in vitro and in animal models.⁴ Contrary to this hypothesis, a small human intervention by Jacob et al.⁶ found that while ceruloplasmin’s oxidase activity was lower in young men fed a high level of vitamin C, it did not depress intestinal copper absorption or overall body copper status. Higher serum vitamin C levels did not result in a decrease in ceruloplasmin levels or its enzymatic activity.⁶ This is consistent with another small human intervention study that reported that 1500 mg/d supplementation with vitamin C had no effect on copper balance or blood levels of copper in young women.⁷ In humans, normal citrate concentrations in the plasma range between 0.05 and 0.3 mM.^8,3

References

1. Kumar A, Archana E, Pai A, Gayathry N, Shenoy RP, Rao A. Serum mineral status and climacteric symptoms in perimenopausal women before and after yoga therapy, an ongoing study. J MidlifeHealth. 2013;4(4):225–229. [PMC]
2. Osaki S, McDermott JA, Frieden E. Proof for the ascorbate oxidase activity of ceruloplasmin. J BiolChem. 1964;239(1):3570–3575. [PubMed]
3. Wang Q, Ji J, Hao S, Zhang M, Li K, Qiao T. Iron together with lipid downregulates protein levels of ceruloplasmin in macrophages associated with rapid foam cell formation. J Atheroscler Thromb.2016;23(10):1201–1211. [PMC]
4. Johnson MA, Fischer JG, Kays SE. Is copper an antioxidant nutrient? Crit Rev Food Sci Nutr.1992;32(1):1–31.
5. Percival SS, Harris ED. Ascorbate enhances copper transport from ceruloplasmin into human K562cells. J Nutr. 1989;119(5):779–784.
6. Jacob RA, Skala JH, Omaye ST, Turnlund JR. Effect of varying ascorbic acid intakes on copper absorption and ceruloplasmin levels in young men. J Nutr. 1987;117(12):2109–2115.
7. Milne DB, Klevay LM, Hunt JR. Effects of copper (Cu) intake and vitamin C supplements on copper and iron nutrition in women (Abstract 3448). Fed Proc. 1987;46(3):908.
8. Koushanpour E, Kriz W. Tubular resorption and secretion: classification based on overall clearance measures. In: Renal physiology: principals, structure, and function, 2nd ed. New York, NY: Springer-Verlag; 1986. pp. 214–239.

Other Helpful References

1. Wang Q, Ji J, Hao S, Zhang M, Li K, Qiao T. Iron together with lipid downregulated protein levels of ceruloplasmin in macrophages associated with rapid foam cell formation. J Atheroscler Thromb.2016;23(10):1201–1211.
2. Lovstad RA. On the mechanism of citrate inhibition of ceruloplasmin ferroxidase activity. Biometals.1996;9(3):273–275.
3. Lovstad RA. A kinetic study of the coupled iron-ceruloplasmin catalyzed oxidation of ascorbate in the presence of albumin. Biometals. 1995;8(4):328–331.
4. Kassouny ME, Coen CH, Bebok ST. Influence of vitamin C and magnesium on calcium, magnesium and copper contents of guinea pig tissues. Int J Vitam Nutr Res. 1985;55(3):295–300.
5. Klenner FR. Observations on the dose and administration of ascorbic acid when employed beyond the range of a vitamin in human pathology. J Orthomolecular Med. 1998;13(4):198–210. [Semantic Scholar]