Copper peptide GHK-Cu
Encyclopedia
The copper peptide GHK-Cu is a naturally occurring copper complex of a glycyl-L-histidyl-L-lysine peptide. Since it has three amino acids it is called tripeptide. The GHK-Cu tripeptide has strong affinity for copper
(II) and was first isolated from human plasma
. It can be found also in saliva
and urine
.
, attraction of immune cells, antioxidant
and anti-inflammatory
effects, stimulation of collagen
and glycosaminoglycan
synthesis in skin fibroblasts and promotion of blood vessels growth. Recent studies indicate its important role in stem cell
biology and anti-tumor defense. Since GHK-Cu plays an important role in skin biology, it is widely used in cosmetics as a reparative and anti-aging ingredient.
in 1973 by Loren Pickart. Pickart noticed that liver tissue obtained from patients aged 60 to 80 years had an increased level of fibrinogen
. However, when liver cells from old patients were incubated in the blood from the younger group, the older cells started functioning in nearly the same way as the younger liver tissue. It turned out that this effect was due to a small peptide factor that behaved similarly to the synthetic peptide glycyl-L-histidyl-L-lysine (GHK). Pickart proposed that this activity in human plasma albumin was a tripeptide glycyl-L-histidyl-L-lysine and that it might function by chelating metal ions.
In 1977, David Schlesinger of the Harvard University Chemistry Department confirmed that the growth modulating peptide isolated by Pickart was a glycyl-L-histidyl-L-lysine peptide.
Further research established that GHK peptide has a strong affinity
for copper and exists in two forms – GHK and GHK-Cu. On the basis of the available data, Pickart proposed that GHK-Cu functions by modulating copper intake into cells.
agent. Pioneers in this field were J.P Borel and F. Maquart from Université de Reims Champagne-Ardenne (France). Between 1988 and 2000, they found that GHK-Cu stimulated the synthesis of collagen
in the skin fibroblasts, increased accumulation of total proteins, glycosaminoglycans and DNA in the dermal wounds in rats. They also found out that the GHK sequence is present in collagen and suggested that the GHK peptide is released after tissue injury. They proposed a class of an emegency response molecules called matrikines, which are released from the extracellular matrix
at the site of an injury .
GHK-Cu also increased synthesis of decorin
– a small proteoglycan
involved in the regulation of collagen synthesis, wound healing regulation and anti-tumor defense.
The same group established that GHK-Cu stimulated both the synthesis of metalloproteinases, the enzymes which break down dermal proteins, and their inhibitors (anti-proteases). The fact that GHK-Cu not only stimulates the production of dermal components, but also regulates their breakdown suggests its regulatory role in the skin remodeling process.
In the dermal wounds of rabbits GHK-Cu facilitated wound healing, causing better wound contraction, faster development of granular tissue and improved angiogenesis
. It also elevated the level of antioxidant enzymes.
GHK-Cu has been found to induce a systemic enhancement of healing in rats, mice, and pigs; that is, the GHK-Cu peptide injected in one area of the body (such as the thigh muscles) improved healing at distant body areas (such as the ears). These treatments strongly increased healing parameters such as collagen production, angiogenesis, and wound closure in both wound chambers and full thickness wounds.
Biotinylated GHK-Cu was incorporated into a collagen membrane, which was used as a wound dressing. This GHK-Cu enriched material stimulated wound contraction and cell proliferation, as well as increased expression of antioxidant enzymes. The same material was tested for wound healing in diabetic rats. GHK-Cu treatment resulted in faster wound contraction and epithelization, higher level of glutathione
and ascorbic acid
, increased synthesis of collagen, and activation of fibroblasts and mast cells. Ischemic open wounds in rats treated with GHK-copper healed faster and had decreased concentration of metalloproteinases 2 and 9 as well as of TNF-beta (a major inflammatory cytokine) compared with vehicle alone or with untreated wounds.
. Axon
regeneration was studied using collagen tubes with incorporated peptides. GHK increased migration of hematogenous cells into collagen tube, production of nerve growth factors, expression of integrins and the rate of regeneration of myelinated nerve fibers. In addition, GHK also increased axon count and proliferation of Schwann cells compared to the control.
protein, the authors concluded that GHK-copper is able to revive the proliferative potential of epidermal stem cells and increase their ability to repair tissue.
Iorio et al. used a repository of transcriptional responses to compounds, the Connectivity Map (cMap), and MANTRA software to explore networks of compounds producing similar transcriptional responses. GHK, as one of the compounds studied, increased mRNA production in 268 genes while suppressing 167.
name: Copper tripeptide-1). Several controlled facial studies confirmed anti-aging, firming and anti-wrinkle activity of copper peptide GHK-Cu.
Abdulghani et al. established that facial cream containing GHK-Cu increased collagen in photoaged skin of 20 female volunteers, performing better than vitamin C
and retinoic acid
.
Leyden et al. conducted 12 weeks facial study of GHK-Cu containing face and eye cream, reporting significant improvement of skin laxity, clarity and appearance, reduced fine lines and the depths of wrinkles and increased skin density and thickness comparing to placebo
. GHK-Cu eye cream performed better than vitamin K cream.
Finkley et al. conducted 12 week facial study on 67 women and reported that GHK-Cu cream applied twice daily improved aged skin appearance, increased thickness, reduced wrinkles and strongly stimulated dermal keratinocyte proliferation as determined by histological analysis of biopsies. The same study found copper peptide GHK-Cu to be non-toxic and non-irritating.
. A commercial product GraftCyte was clinically proven to improve hair transplantation
, outcome. Another hair product that contains copper-peptide GHK-Cu is Tricomin
.
was replaced with a synthetic amino acid, established that the amino acid glycine
plays major role in copper binding, while lysine
can interact with copper only at alkaline pH. At physiological pH, lysine is able to interact with a cellular receptor. The ability of GHK to interact both with copper and with a cellular receptor allows it to transfer copper into and from cells. The small size of GHK permits speedy traveling in extracellular space and its easy access to cellular receptors.
(cytochrome c oxidase
), antioxidant defense (ceruloplasmin, superoxide dismutase (SOD), detoxification (metallothioneins), blood clotting (blood clotting factors V and VIII), melanin production (tyrosinase) and the connective tissue formation (lysyl peroxidase). Copper is required for iron metabolism, oxygenation, neurotransmission
, embryonic development and many other essential biological processes. Another function of copper is signaling – for example, stem cells require a certain level of copper in the media to start their differentiation
into cells needed for repair. Thus, GHK-Cu’s ability to bind copper and to modulate its tissue level is a key factor determining its biological activity.
Copper
Copper is a chemical element with the symbol Cu and atomic number 29. It is a ductile metal with very high thermal and electrical conductivity. Pure copper is soft and malleable; an exposed surface has a reddish-orange tarnish...
(II) and was first isolated from human plasma
Plasma
Plasma may refer to:* Blood plasma, the yellow-colored liquid component of blood, in which blood cells are suspended* Plasma , an ionized state of matter similar to a gas...
. It can be found also in saliva
Saliva
Saliva , referred to in various contexts as spit, spittle, drivel, drool, or slobber, is the watery substance produced in the mouths of humans and most other animals. Saliva is a component of oral fluid. In mammals, saliva is produced in and secreted from the three pairs of major salivary glands,...
and urine
Urine
Urine is a typically sterile liquid by-product of the body that is secreted by the kidneys through a process called urination and excreted through the urethra. Cellular metabolism generates numerous by-products, many rich in nitrogen, that require elimination from the bloodstream...
.
Overview
The copper peptide GHK-Cu is a naturally occurring human tripeptide. In plasma, the level of GHK-Cu is about 200 ng/ml at age 20. By the age of 60, the level drops to 80 ng/ml. Scientific studies conducted in different research laboratories around the world have established that human tripeptide GHK-Cu possesses a plethora of biological actions including activation of wound healingWound healing
Wound healing, or cicatrisation, is an intricate process in which the skin repairs itself after injury. In normal skin, the epidermis and dermis exists in a steady-state equilibrium, forming a protective barrier against the external environment...
, attraction of immune cells, antioxidant
Antioxidant
An antioxidant is a molecule capable of inhibiting the oxidation of other molecules. Oxidation is a chemical reaction that transfers electrons or hydrogen from a substance to an oxidizing agent. Oxidation reactions can produce free radicals. In turn, these radicals can start chain reactions. When...
and anti-inflammatory
Anti-inflammatory
Anti-inflammatory refers to the property of a substance or treatment that reduces inflammation. Anti-inflammatory drugs make up about half of analgesics, remedying pain by reducing inflammation as opposed to opioids, which affect the central nervous system....
effects, stimulation of collagen
Collagen
Collagen is a group of naturally occurring proteins found in animals, especially in the flesh and connective tissues of mammals. It is the main component of connective tissue, and is the most abundant protein in mammals, making up about 25% to 35% of the whole-body protein content...
and glycosaminoglycan
Glycosaminoglycan
Glycosaminoglycans or mucopolysaccharides are long unbranched polysaccharides consisting of a repeating disaccharide unit. The repeating unit consists of a hexose or a hexuronic acid, linked to a hexosamine .-Production:Protein cores made in the rough endoplasmic reticulum are posttranslationally...
synthesis in skin fibroblasts and promotion of blood vessels growth. Recent studies indicate its important role in stem cell
Stem cell
This article is about the cell type. For the medical therapy, see Stem Cell TreatmentsStem cells are biological cells found in all multicellular organisms, that can divide and differentiate into diverse specialized cell types and can self-renew to produce more stem cells...
biology and anti-tumor defense. Since GHK-Cu plays an important role in skin biology, it is widely used in cosmetics as a reparative and anti-aging ingredient.
History
Copper peptide GHK-Cu was isolated from human plasma albuminAlbumin
Albumin refers generally to any protein that is water soluble, which is moderately soluble in concentrated salt solutions, and experiences heat denaturation. They are commonly found in blood plasma, and are unique to other blood proteins in that they are not glycosylated...
in 1973 by Loren Pickart. Pickart noticed that liver tissue obtained from patients aged 60 to 80 years had an increased level of fibrinogen
Fibrinogen
Fibrinogen is a soluble plasma glycoprotein, synthesised by the liver, that is converted by thrombin into fibrin during blood coagulation. This is achieved through processes in the coagulation cascade that activate the zymogen prothrombin to the serine protease thrombin, which is responsible for...
. However, when liver cells from old patients were incubated in the blood from the younger group, the older cells started functioning in nearly the same way as the younger liver tissue. It turned out that this effect was due to a small peptide factor that behaved similarly to the synthetic peptide glycyl-L-histidyl-L-lysine (GHK). Pickart proposed that this activity in human plasma albumin was a tripeptide glycyl-L-histidyl-L-lysine and that it might function by chelating metal ions.
In 1977, David Schlesinger of the Harvard University Chemistry Department confirmed that the growth modulating peptide isolated by Pickart was a glycyl-L-histidyl-L-lysine peptide.
Further research established that GHK peptide has a strong affinity
Chemical affinity
In chemical physics and physical chemistry, chemical affinity is the electronic property by which dissimilar chemical species are capable of forming chemical compounds...
for copper and exists in two forms – GHK and GHK-Cu. On the basis of the available data, Pickart proposed that GHK-Cu functions by modulating copper intake into cells.
Biochemical Studies
In the late 1980s, copper peptide GHK-Cu started attracting attention as a promising wound healingWound healing
Wound healing, or cicatrisation, is an intricate process in which the skin repairs itself after injury. In normal skin, the epidermis and dermis exists in a steady-state equilibrium, forming a protective barrier against the external environment...
agent. Pioneers in this field were J.P Borel and F. Maquart from Université de Reims Champagne-Ardenne (France). Between 1988 and 2000, they found that GHK-Cu stimulated the synthesis of collagen
Collagen
Collagen is a group of naturally occurring proteins found in animals, especially in the flesh and connective tissues of mammals. It is the main component of connective tissue, and is the most abundant protein in mammals, making up about 25% to 35% of the whole-body protein content...
in the skin fibroblasts, increased accumulation of total proteins, glycosaminoglycans and DNA in the dermal wounds in rats. They also found out that the GHK sequence is present in collagen and suggested that the GHK peptide is released after tissue injury. They proposed a class of an emegency response molecules called matrikines, which are released from the extracellular matrix
Extracellular matrix
In biology, the extracellular matrix is the extracellular part of animal tissue that usually provides structural support to the animal cells in addition to performing various other important functions. The extracellular matrix is the defining feature of connective tissue in animals.Extracellular...
at the site of an injury .
GHK-Cu also increased synthesis of decorin
Decorin
Decorin is a proteoglycan on average 90 - 140 kilodaltons in size.It belongs to the small leucine-rich proteoglycan family and consists of a protein core containing leucine repeats with a glycosaminoglycan chain consisting of either chondroitin sulfate or dermatan sulfate .Decorin is a small...
– a small proteoglycan
Proteoglycan
Proteoglycans are proteins that are heavily glycosylated. The basic proteoglycan unit consists of a "core protein" with one or more covalently attached glycosaminoglycan chain. The point of attachment is a Ser residue to which the glycosaminoglycan is joined through a tetrasaccharide bridge...
involved in the regulation of collagen synthesis, wound healing regulation and anti-tumor defense.
The same group established that GHK-Cu stimulated both the synthesis of metalloproteinases, the enzymes which break down dermal proteins, and their inhibitors (anti-proteases). The fact that GHK-Cu not only stimulates the production of dermal components, but also regulates their breakdown suggests its regulatory role in the skin remodeling process.
Wound healing in animals
A series of animal experiments established pronounced wound healing activity of copper peptide GHK-Cu.In the dermal wounds of rabbits GHK-Cu facilitated wound healing, causing better wound contraction, faster development of granular tissue and improved angiogenesis
Angiogenesis
Angiogenesis is the physiological process involving the growth of new blood vessels from pre-existing vessels. Though there has been some debate over terminology, vasculogenesis is the term used for spontaneous blood-vessel formation, and intussusception is the term for the formation of new blood...
. It also elevated the level of antioxidant enzymes.
GHK-Cu has been found to induce a systemic enhancement of healing in rats, mice, and pigs; that is, the GHK-Cu peptide injected in one area of the body (such as the thigh muscles) improved healing at distant body areas (such as the ears). These treatments strongly increased healing parameters such as collagen production, angiogenesis, and wound closure in both wound chambers and full thickness wounds.
Biotinylated GHK-Cu was incorporated into a collagen membrane, which was used as a wound dressing. This GHK-Cu enriched material stimulated wound contraction and cell proliferation, as well as increased expression of antioxidant enzymes. The same material was tested for wound healing in diabetic rats. GHK-Cu treatment resulted in faster wound contraction and epithelization, higher level of glutathione
Glutathione
Glutathione is a tripeptide that contains an unusual peptide linkage between the amine group of cysteine and the carboxyl group of the glutamate side-chain...
and ascorbic acid
Ascorbic acid
Ascorbic acid is a naturally occurring organic compound with antioxidant properties. It is a white solid, but impure samples can appear yellowish. It dissolves well in water to give mildly acidic solutions. Ascorbic acid is one form of vitamin C. The name is derived from a- and scorbutus , the...
, increased synthesis of collagen, and activation of fibroblasts and mast cells. Ischemic open wounds in rats treated with GHK-copper healed faster and had decreased concentration of metalloproteinases 2 and 9 as well as of TNF-beta (a major inflammatory cytokine) compared with vehicle alone or with untreated wounds.
Human Trials
A 2% GHK gel showed promising results in treatment of 120 diabetic patients, increasing the percentage of ulcer closure from 60.8% to 98.5%, and decreasing the percentage of infection from 34% to 7%. The rate of healing was three times greater with GHK. However, a 0.4% GHK-Cu cream failed to reach therapeutic goal in treatment of venous ulcers. It is possible that that failure was due to a presence of bacterial film on hospital wounds that led to a fast degradation of the peptide. Recently, a second generation of breakdown resistant copper peptides was developed.DNA Repair
Radioactive anti-cancer treatment slows cell replication by breaking DNA strands. A recent study showed GHK-Cu's ability to restore function of irradiated fibroblasts to that of intact cells. The researchers used cultured human fibroblasts obtained from cervical skin that was either intact or exposed to radioactive treatment (5000 rad). At a very low (1 nanomolar) concentration, GHK-Cu stimulated irradiated fibroblasts growth and increased their production of growth factors bFGF and VGF to the point where it became even higher than that of both the irradiated and intact control cells.Nerve Regeneration
In 2005, Ahmed et al. demonstrated that GHK promotes nerve regenerationNerve regeneration
Neuroregeneration refers to the regrowth or repair of nervous tissues, cells or cell products. Such mechanisms may include generation of new neurons, glia, axons, myelin, or synapses. Neuroregeneration differs between the peripheral nervous system and the central nervous system by the functional...
. Axon
Axon
An axon is a long, slender projection of a nerve cell, or neuron, that conducts electrical impulses away from the neuron's cell body or soma....
regeneration was studied using collagen tubes with incorporated peptides. GHK increased migration of hematogenous cells into collagen tube, production of nerve growth factors, expression of integrins and the rate of regeneration of myelinated nerve fibers. In addition, GHK also increased axon count and proliferation of Schwann cells compared to the control.
Effect on Stem Cells
In 2009, a group of researchers from the Seoul National University (Republic of Korea) demonstrated that the copper-peptide GHK-Cu stimulated proliferation of keratinocytes and increased expression of integrins and p63 protein in the epidermal stem cells. Since p63 is considered to be an important marker of stem cell and anti-senescenceSenescence
Senescence or biological aging is the change in the biology of an organism as it ages after its maturity. Such changes range from those affecting its cells and their function to those affecting the whole organism...
protein, the authors concluded that GHK-copper is able to revive the proliferative potential of epidermal stem cells and increase their ability to repair tissue.
Anti-Cancer Effect
In 2010, Hong Y. et al. (Department of Colorectal Surgery, Singapore General Hospital, Singapore) demonstrated that GHK-Cu is able to reverse the expression of certain genes involved in metastatic spreading of colon cancer. GHK-Cu was effective at a very low concentration - 1mkM.Genomic Studies
Recent genomic research suggests that GHK directly modulates gene expression, which may explain the diversity of its biological actions.Iorio et al. used a repository of transcriptional responses to compounds, the Connectivity Map (cMap), and MANTRA software to explore networks of compounds producing similar transcriptional responses. GHK, as one of the compounds studied, increased mRNA production in 268 genes while suppressing 167.
Facial Studies
Copper peptide GHK-Cu is widely used in anti-aging cosmetics (INCIINCI
The International Nomenclature of Cosmetic Ingredients, abbreviated INCI, is a system of names for waxes, oils, pigments, chemicals, and other ingredients of soaps, cosmetics, and the like, based on scientific names and other Latin and English words...
name: Copper tripeptide-1). Several controlled facial studies confirmed anti-aging, firming and anti-wrinkle activity of copper peptide GHK-Cu.
Abdulghani et al. established that facial cream containing GHK-Cu increased collagen in photoaged skin of 20 female volunteers, performing better than vitamin C
Vitamin C
Vitamin C or L-ascorbic acid or L-ascorbate is an essential nutrient for humans and certain other animal species. In living organisms ascorbate acts as an antioxidant by protecting the body against oxidative stress...
and retinoic acid
Retinoic acid
Retinoic acid is a metabolite of vitamin A that mediates the functions of vitamin A required for growth and development. Retinoic acid is required in chordate animals which includes all higher animals from fishes to humans...
.
Leyden et al. conducted 12 weeks facial study of GHK-Cu containing face and eye cream, reporting significant improvement of skin laxity, clarity and appearance, reduced fine lines and the depths of wrinkles and increased skin density and thickness comparing to placebo
Placebo
A placebo is a simulated or otherwise medically ineffectual treatment for a disease or other medical condition intended to deceive the recipient...
. GHK-Cu eye cream performed better than vitamin K cream.
Finkley et al. conducted 12 week facial study on 67 women and reported that GHK-Cu cream applied twice daily improved aged skin appearance, increased thickness, reduced wrinkles and strongly stimulated dermal keratinocyte proliferation as determined by histological analysis of biopsies. The same study found copper peptide GHK-Cu to be non-toxic and non-irritating.
Hair Growth
Copper peptide GHK-Cu and its analogues were found to strongly stimulate hair growth. The efficiency of synthetic analog of GHK-Cu was similar to that of 5% minoxidilMinoxidil
Minoxidil is an antihypertensive vasodilator medication which also slows or stops hair loss and promotes hair regrowth. Now off-patent, it is available over-the-counter for the treatment of androgenic alopecia. Minoxidil must be used indefinitely for continued support of existing hair follicles and...
. A commercial product GraftCyte was clinically proven to improve hair transplantation
Hair transplantation
Hair transplantation is a surgical technique that involves moving individual hair follicles from one part of the body to bald or balding parts . It is primarily used to treat male pattern baldness. It this case, grafts containing hair follicles that are genetically resistant to balding are...
, outcome. Another hair product that contains copper-peptide GHK-Cu is Tricomin
Tricomin
Tricomin is a purported non-drug alternative to prevent hair loss and , with a copper peptide as a key ingredient. The product is manufactured by the ProCyte corporation....
.
Copper Binding
Research of the copper binding properties of GHK and two synthetic peptides, in which histidineHistidine
Histidine Histidine, an essential amino acid, has a positively charged imidazole functional group. It is one of the 22 proteinogenic amino acids. Its codons are CAU and CAC. Histidine was first isolated by German physician Albrecht Kossel in 1896. Histidine is an essential amino acid in humans...
was replaced with a synthetic amino acid, established that the amino acid glycine
Glycine
Glycine is an organic compound with the formula NH2CH2COOH. Having a hydrogen substituent as its 'side chain', glycine is the smallest of the 20 amino acids commonly found in proteins. Its codons are GGU, GGC, GGA, GGG cf. the genetic code.Glycine is a colourless, sweet-tasting crystalline solid...
plays major role in copper binding, while lysine
Lysine
Lysine is an α-amino acid with the chemical formula HO2CCH4NH2. It is an essential amino acid, which means that the human body cannot synthesize it. Its codons are AAA and AAG....
can interact with copper only at alkaline pH. At physiological pH, lysine is able to interact with a cellular receptor. The ability of GHK to interact both with copper and with a cellular receptor allows it to transfer copper into and from cells. The small size of GHK permits speedy traveling in extracellular space and its easy access to cellular receptors.
Biological Significance
Copper is a transitional metal that is vital for all eukaryotic organisms from microbes to humans. A dozen enzymes (cuproenzymes) use changes in copper oxidation state to catalyze important biochemical reactions including cellular respirationCellular respiration
Cellular respiration is the set of the metabolic reactions and processes that take place in the cells of organisms to convert biochemical energy from nutrients into adenosine triphosphate , and then release waste products. The reactions involved in respiration are catabolic reactions that involve...
(cytochrome c oxidase
Cytochrome c oxidase
The enzyme cytochrome c oxidase or Complex IV is a large transmembrane protein complex found in bacteria and the mitochondrion.It is the last enzyme in the respiratory electron transport chain of mitochondria located in the mitochondrial membrane...
), antioxidant defense (ceruloplasmin, superoxide dismutase (SOD), detoxification (metallothioneins), blood clotting (blood clotting factors V and VIII), melanin production (tyrosinase) and the connective tissue formation (lysyl peroxidase). Copper is required for iron metabolism, oxygenation, neurotransmission
Neurotransmission
Neurotransmission , also called synaptic transmission, is the process by which signaling molecules called neurotransmitters are released by a neuron , and bind to and activate the receptors of another neuron...
, embryonic development and many other essential biological processes. Another function of copper is signaling – for example, stem cells require a certain level of copper in the media to start their differentiation
Cellular differentiation
In developmental biology, cellular differentiation is the process by which a less specialized cell becomes a more specialized cell type. Differentiation occurs numerous times during the development of a multicellular organism as the organism changes from a simple zygote to a complex system of...
into cells needed for repair. Thus, GHK-Cu’s ability to bind copper and to modulate its tissue level is a key factor determining its biological activity.