Copper in Skincare

By Dr Charlene DeHaven / 01 Dec 2015

Dr Charlene DeHaven details the uses and benefits of copper in advanced skincare

Copper is one of the essential ‘trace metals’ required in small amounts for proper functioning of the human body and its various macro and microsystems, including enzyme systems. Other necessary trace metals include zinc, selenium, magnesium, and manganese. Minimum dietary requirements must be met for each trace metal. These requirements are small, but if deficient amounts are ingested, many systems fail to work properly.1,2 In addition, copper is involved with energy creation via its role in cytochrome oxidase, a superfamily of proteins, which act as the terminal enzymes of respiratory chains. All living cells in the human body generate energy in order to function. Copper is required in mitochondria, the tiny energy factories within each cell that are responsible for metabolism and energy creation.1 For skin, copper is perhaps best known as a required cofactor in collagen synthesis. It is also a necessary metal in a number of other biochemical reactions occurring in the skin, as listed in Figure 1.3 

Copper may exist in a metallic form or an ionic form. The metallic form of copper is the type many think of when visualising this metal – however, copper in metallic form cannot be used by biologic systems. In order for humans and other organisms to benefit from copper, it must be present in ionic form. Ionic copper can be joined to enzyme systems via chemical bonds and is the only form that is active in the human body.4 Ionic forms of copper look very different from copper metal; these have no ‘metallic’ appearance because the copper in them is chemically bound to other substances. Medical literature details uses of copper ions as antimicrobials with potential to combat a variety of possible infectious processes including; bacteria,5 herpes viruses,6 leishmaniasis,7 and other conditions where infectious processes are implicated such Propionibacterium acnes.8

The role of copper within cosmeceuticals

There are numerous potential applications for using copper in aesthetics; the key factors are outlined below:

Potentiating effects on collagen synthesis

Collagen is the most prevalent protein in the body and most collagen is found in the skin (Figure 2). Collagen serves as the structural framework for numerous tissues including skin, bone, teeth, tendons, and all other connective tissues.9 Since both vitamin C and copper are necessary for the formation of healthy collagen, combining both ingredients in a single formula would be ideal. Studies have indicated that combining copper and vitamin C together results in a chemical reaction between the two substances, causing a decrease in antioxidant activity,10 although, one product claims to have combined the two successfully.11 Growth factors such as copper tripeptide-1 also increase collagen synthesis.12 This growth factor is a tripeptide composed of the three amino acids; glycine, histidine, and lysine. This natural molecule, found in human skin and other tissues, mediates its effect of encouraging collagen

Figure 2: The triple helix of collagen, composed of two alpha1 strands and one alpha2 strand

synthesis via decorin,13 a molecule intimately involved with the architecturally correct synthesis of collagen. Copper tripeptide-1 also affects matrix metalloproteinase (MMP) enzymes.14,15 This growth factor belongs to a group of emergency response molecules that come to the body’s aid in times of stress, including wound healing,16 tissue remodeling,17 stem cell anti- senescence,18 ageing,19,20 post-procedure,21,22 inflammation and oxidative stress,23 and infection. Copper tripeptide-1 also has anti- tumorigenic properties, while at the same time encouraging the growth and normal development of healthy cell lines.24,25

Wound healing

Copper metal ions have been found in higher concentrations around healing wounds and thus are implicated in wound healing and inflammatory processes.26 The topical application of copper ion-containing ointments has been associated with improved wound healing.27 In addition there is a huge body of scientific evidence supporting the essential role of copper tripeptide-1 growth factor in the acceleration of wound healing (Figure 3).10,12,13,17 This compound is released during tissue injury to signal repair processes to begin. 

Figure 3: Two identical full-thickness incisions were made in the thighs of a 54-year-old female, sutures removed at seven days, application of copper serum began, digital photos taken at three months and six months post treatment.

Antioxidant support system

Copper, in particular copper tripeptide-1 growth factor, has shown significant impact in optimising antioxidant protection within formulations (Figure 4).

Equally it has shown to provide a pivotal role in a new wave of antioxidants. Superoxide dismutase (SOD), which previously required intravenous administration for delivery, is now available in topical form. SOD is one of three enzymatic antioxidants made by the human body. All were designed through evolutionary processes to neutralise free radical damage.24 This group of antioxidants is unique in several aspects; they are effective in very tiny amounts and are not inactivated during the redox process. Furthermore, they are not used up while combating free radical processes and persist in the body for long periods of time, unlike other non-enzymatic antioxidants, such as vitamin C.28 A study has shown that copper assists SOD for proper functioning in its antioxidant role.29

Figure 4: ORAC (Oxygen Radical Absorption Capacity) measures total lipophilic antioxidant capacity. Testing independently performed by Brunswick Labs. Image provided courtesy of INNOVATIVE SKINCARE. 

Role in melanin synthesis

Melanin is designed to give some protection against photodamage. Copper is necessary for melanin synthesis within melanocytes, which are found scattered along the Dermal-Epidermal Junction (DEJ) in the basal layer of epidermis.1 Equally tyrosinase, the enzymatic partner for copper, is the most crucial enzyme required in melanin synthesis, as its action is the rate-limiting step in melanin production.30

Tissue remodelling

Copper tripeptide-1 and other forms of copper are active for tissue remodelling, which is the return of injured tissue to normal architecture and function. It increases keratinocyte proliferation and normal collagen synthesis, improves skin thickness, skin elasticity, firmness and wrinkles.13,15,16 Through the effects of decorin, new collagen made in injured tissue assumes the correct anatomical configuration and structure rather than a disorganised scar.31

Conclusion: All good things in moderation

Although copper is required for human life and for many biologic processes, too much of a good thing is not positive. Ingesting large amounts of copper as a supplement can be harmful and even toxic.32 Both copper and iron have the potential to act as pro-oxidants and increase free radical damage if found in excess.10 However, providing copper in correct amounts can certainly assist many aspects of skin functionality, improve skin health, and maintain youthful vitality of skin appearance. 

References
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  3. Stipanuk MH & Caudill MA Biochemical, Physiological, and Molecular Aspects of Human Nutrition, eds. Zinc, Copper, and Manganese. Grider A. 2013. Elsevier: USA. p830

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  5. Dlewell A, Barnes M, Endres JR, Ahmed M, Ghambeer DK. J, Walkenhorst WF, Sundrud JN, Laviolette JM. Additivity and synergy between an antimicrobial peptide and inhibitors ions Biochim Biophys Acta. 2014 Sep. 1839(9):pp2234-42. Epub 2014

  6. Drugs Dermatol. Efficacy and tolerability assessment of a topical formulation containing copper sulfate and hypericum perforatum on patients with herpes skin lesions: a comparative, randomized controlled trial. 2012 Feb. 11(2):pp209-15

  7. Peniche AG, Renslo AR, Melby PC, Travi BL, Antileishmanial activity of disulfiram and thiuram disulfide analogs in an ex vivo model system is selectively enhanced by the addition of divalent metal ions. Antimicrob Agents Chemother. 2015 Aug 3. Epub ahead of print

  8. Stephens TJ, McCook JP, Herndon JH Jr. J Pilot study of topical copper chlorophyllin complex in subjects with facial acne and large pores, Drugs Dermatol. 2015 Jun. 14(6):pp589-92.

  9. Diegelmann RF, Medscape, Wounds, Collagen Metabolism 2001;13(5) http://www.medscape.com/viewarticle/423231

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  11. iS Clinical, Super Serum Advance, n.d, https://www.isclinical.co.uk/super-serum-results

  12. Maquart FX, Pickart L, Laurent M, Gillery P, Monboisse JC, Borel JP, Stimulation of collagen synthesis in fibroblast cultures by the tripeptide-copper complex glycyl-L-histidyl-L-lysine-Cu2+. FEBS Lett. 1988 Oct 10. 238(2):pp343-6.

  13. Kinsella MG, Bressler SL, Wight TN. The regulated synthesis of versican, decorin, and biglycan: extracellular matrix proteoglycans that influence cellular phenotype. Crit Rev Eukaryot Gene Expr. 2004. 14(3):pp203-34.

  14. Simeon A, Monier F, Emonard H, Gillery P, Birembaut P, Hornebeck W, Maquart FX, Expression and activation of matrix metalloproteinases in wounds: modulation by the tripeptide-copper complex glycyl-L-histidyl-L-lysine-Cu2+. J Invest Dermatol. 1999 Jun. 112(6):pp957-64.

  15. Simeon A, Emonard H, Hornebeck W, Maquart FX, The tripeptide-copper complex glycyl-L- histidyl-L-lysine-Cu2+ stimulates matrix metalloproteinase-2 expression by fiboblast cyultures. Life Sci. 2000 Sep 22. 67(18):pp2257-65.

  16. Pickart L, Published studies on tissue and skin remodeling copper-peptides: copper peptide studies on skin renewal, wound healing, and hair growth. Skinbiology.com (2014). http://skinbiology.com/copperpeptideregeneration.html

  17. Pickart L, The human tri-peptide GHK and tissue remodeling. J BiomaterSciPolym Ed. 2008. 19(8):pp969-88.

  18. Choi HR, Kang YA, Ryoo SJ, Shin JW, Na JI, Huh CH, Park KC, Stem cell recovering effect of copper-free GHK in skin, J Pept Sci. 2012 Nov. 18(11):pp685-90. 

  19. Leyden J, Stephens T, Finkey MB, Appa Y, Barkovic S, Skin care benefits of copper peptide containing facial cream. Amer Academy Dermat Meeting. 2002 Feb. Abstract pp68-69. 

  20. Pickart L. Klatz R, Goldman R (eds.) The human tripeptide GHK (glycyl-L-histidyl-L-lysine), the copper switch and the treatment of the degenerative conditions of aging. Anti-Aging Therapeutics Vol XI. American Academy of Medicine:Chicago IL. 2009. pp301-3012. 

  21. Miller TR, Wagner JD, Baack BR, Eisbach KJ, Effects of topical copper tripeptide complex on CO2 laser-resurfaced skin. Arch Facial Plast Surg. 2006 Jul-Aug. 8(4):pp252-9.

  22. Miller TR, Wagner JD, Baack BR, Eisbach KJ, Effects of topical copper tripeptide complex on CO2 laser-resurfaced skin. Arch Facial Plast Surg. 2006 Jul-Aug. 8(4):pp252-9.

  23. Miller DM, DeSilva D, Pickart L, Aust SD, Effects of glycyl-histidyl-lysyl chelated Cu(II) on ferritin dependent lipid peroxidation. Adv Exp Med Biol. 1990. 264:pp79-84.

  24. Matalka LE, Ford A, Unlap MT, The tripeptide, GHK, induces programmed cell death in SH-SY5Y neuroblastoma cells. J Biotechnol Biomater. 2012. 2:p144.

  25. Hong Y, Downey T, Eu KW, Koh PK, Cheah PY, A ‘metastasis-prone’ signature for early-stage mismatch-repair proficient sporadic colorectal cancer patients and its implications for possible therapeutics. Clin Exp Metastasis. 2010 Feb 9.

  26. Miratschijski U, Martin A, Jorgensen LN, Sampson B, Agren MS, Zinc, copper, and selenium tissue levels and their relation to subcutaneous abscess, minor surgery, and wound healing in humans. Biol Trace Elem Res. 2013 Jun. 153(1-3):pp76-83. Epub 2013 Apr 18.

  27. Frangoulis M, Georgiou P, Chrisostomidis C, Perrea D, Dontas I, Kavantzas N, Kostakis A, Papadopoulos O, Rat epigastric flap survival and VEGF expression after local copper application. Plast Reconstr Surg. 2007 Mar. 119(3):pp837-43.

  28. Fukai, T. Ushino-Fukai, M. Antioxidants & Redox signaling, Superoxide Dismutases: Role in Redox Signalling, Vascular Function, and Diseases, 2011 Sep 15; 15(6): 1583–1606 http://www.ncbi.nlm. nih.gov/pmc/articles/PMC3151424/

  29. Abreu IA, Cabelli DE, Superoxide dismutases – a review of the metal-associated mechanistic variations. Biochim Biophys Acta. 2010 Feb. 1804(2):pp263-74.

  30. Casanola-Martin GM, Le-Thi-Thu H, Marrero-Ponce Y, Castillo-Garit JA, Torrens F, Rescigno A, Abad C, Khan MT, Tyrosinase enzyme: 1. An overview on a pharmacologic target. Curr Top Med Chem. 2014. 14(12):pp1494-501.

  31. Kinsella MG, Bressler SL, Wight TN. The regulated synthesis of versican, decorin, and biglycan: extracellular matrix proteoglycans that influence cellular phenotype. Crit Rev Eukaryot Gene Expr. 2004. 14(3):203-34

  32. Araya, M; McGoldrick, MC; Klevay, L M.; Strain, J.J.; Robson, P; Nielsen, Forrest; O, Manuel; Pizarro, F; Johnson, L; Poirier, K A. (2001). Determination of an Acute No-Observed-Adverse- Effect Level (NOAEL) for Copper in Water. Regulatory Toxicology and Pharmacology 34 (2): 137–45. doi:10.1006/rtph.2001.1492. PMID 11603956. 

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