How to increase pheomelanin production?

How to increase pheomelanin production?

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How can you increase the pheomelanin production in your body, while decreasing the eumelanin production? In other words, shifting the balance towards pheomelanin.

From what I see, sulfur and cysteine can help with this. MSM and glutathione caps can be a good way to do this, since these are used for skin lightening.

But is there another way? Something more scientific? Like deactivating the MC1R? Is that even possible?

Thank you!

Since Eumelanin is the protective form of melanin and there is some research available that Pheomelanin contributes to the generation of reactive oxygen species which are harmful to the cell (see reference 1, which contains a lot of further references on this topic), I don't see any reason to do so, but ok. Additionally removing Eumelanin from your skin will lead to a higher risk for skin cancers as Melanoma. Let's think through this:

If we look at the biosynthesis pathway of the Melanins, they both start with the same two reactions (see the figure from here):

The routs parts at the DOPAquinone, which in the presence of Gluthathione or Cysteine goes into the pheomelanin direction. The concentration of Cysteine available to the cell needs to be higher than 0,76 µM (see references 2 and 3 for details), otherwise the reaction goes exclusively into the Eumelanin direction.

There are some skin whitening (or better lightening) products available which contain L-Cysteine or GSH. This will work to some extend, but once the level drops enough, the ratio will shift back to the more natural ratio between Eumelanin and Pheomelanin. There is also no data available on the risks of doing this, so I would strongly advocate against it. See the review in reference 4 for details and additional references on this topic.

If you now think, ok, taking some pills is enough, I would call this a false hope, since this process is highly regulated. This happens on one part through external signaling through the MC1R receptor (which as you already mentioned is of importance here) and also through the availability of key enzymes in the process as well as stability of them and their regulation.

Signaling through the MC1R receptor is highly important for pigmentation and also the amount of enzymes available (the transcription factor MITF is regulated by it). If the signaling is strong, the cysteine storage is soon depleted bringing on the production of Eumelanin. If this signaling is weak this will not happen and the production of pheomelanin is favoured. Mutations in MC1R are the reason for people having red hair and and fair skin. See reference 5 and 6.

Interfering with the signaling cascade which is activated by MC1R is certainly not a good idea either, since this will interfere with other processes in the cell as well. These pathways are also disregulated in cancers, so I would not touch these.

Summarizing I think there will only be a way of influencing this by taking some supplements, but how safe this is, is unknown. All the other possible ways are certainly more dangerous.


  1. How does pheomelanin synthesis contribute to melanomagenesis?: Two distinct mechanisms could explain the carcinogenicity of pheomelanin synthesis.
  2. Rate constants for the first two chemical steps of eumelanogenesis.
  3. Chemistry of mixed melanogenesis--pivotal roles of dopaquinone.
  4. Systemic skin whitening/lightening agents: What is the evidence?
  5. UV signaling pathways within the skin
  6. The melanocortin-1 receptor: red hair and beyond.

V. Setaluri, A. Jayanthy, in Brenner’s Encyclopedia of Genetics (Second Edition), 2013. Pigment-Type Switching. Low melanosome pH favors pheomelanin formation and high pH favors eumelanin. Therefore, gene(s) encoding the melanosomal proteins that control the internal pH of the melanosomes can play a critical role in the determination of coat color.

2 .Caused due to high level of pheomelanin, Scotland’s cx»pulation has

A phaeochromocytoma can cause the adrenal glands to produce too much of these hormones, which often results in problems such as heart palpitations and high blood pressure. Symptoms of a phaeochromocytoma The symptoms of a phaeochromocytoma tend to be unpredictable, often occurring in sudden attacks lasting from a few minutes to an hour.

3 .Caused due to high level of pheomelanin, Scotland’s cx»pulation has

Full editorial control rests with Skin Cancer UK, however the final content has been reviewed for factual accuracy by Roche Products Ltd. Funding for this project has been provided by Roche Products Ltd. Page 1 of 8 Malignant melanoma in Scotland Introduction Skin cancer is the most common cancer in Scotland.

4 .Caused due to high level of pheomelanin, Scotland’s cx»pulation has

Since Eumelanin is the protective form of melanin and there is some research available that Pheomelanin contributes to the generation of reactive oxygen species which are harmful to the cell (see reference 1, which contains a lot of further references on this topic), I don’t see any reason to do so, but ok.

5 .Caused due to high level of pheomelanin, Scotland’s cx»pulation has

Scotland has the highest proportion of them in the world. Around 13% of the population has it, with 40% carrying the recessive gene. It appears in people with two copies of a recessive allele on…

6 .Caused due to high level of pheomelanin, Scotland’s cx»pulation has

Phaeochromocytoma. Phaeochromocytomas are rare tumours that start in the inner section of the adrenal gland (the medulla). Treatment depends on several factors, including the size of your tumour, whether it has spread and your general health and fitness.

7 .Caused due to high level of pheomelanin, Scotland’s cx»pulation has

pheomelanin. Blonde is only found in about 2% of the world’s population. It is due to very small amounts of melanin. Slight amounts of black, brown, and red make for all the variations we see in blonds – such as ash, flaxen, and strawberry blond. Red hair is the rarest of all, about 1% of the world. It is due to high levels of pheomelanin plus low

8 .Caused due to high level of pheomelanin, Scotland’s cx»pulation has

The Dark side of the Highlands. There are also darker sides to the history of the Highlands and one of them is the “Highlands of the clans” with their chieftains, the battles, the massacre’s and the bloodsheds, portrayed in history books and later turned into movies we all know such as William Wallace and Rob Roy McGregor.A good example is the massacre of Glen Coe in 1692 when the …

9 .Caused due to high level of pheomelanin, Scotland’s cx»pulation has

National Records of Scotland. The leading causes of death in 2018 were: Ischaemic heart disease: 6,615 (11.3%) Dementia and Alzheimer’s disease: 6,484 (11.1%) Lung cancer: 3,980 (6.8%) Cerebrovascular disease (including stroke): 3,831 (6.5%) Chronic lower respiratory diseases (eg bronchitis and emphysema): 3,469 (5.9%) This analysis is based on a list of causes developed by the World Health …

10 .Caused due to high level of pheomelanin, Scotland’s cx»pulation has

Overview. Cephalohematoma (CH) is a collection of blood between a baby’s scalp and the skull. Damaged blood vessels release the blood, and the blood pools into a mass under the skin of the scalp.

Females mate with males with diminished pheomelanin-based coloration in the Eurasian nuthatch Sitta europaea

Sexual selection can drive the evolution of phenotypic traits because of female preferences for exaggerated trait expression in males. Sexual selection can also lead to the evolutionary loss of traits, a process to which female preferences for diminished male trait expression are hypothesized to contribute. However, empirical evidence of female preferences for diminished male traits is virtually lacking. Eurasian nuthatches Sitta europaea provide an opportunity to test this possibility, as a chestnut flank patch produced by the pigment pheomelanin is present since the first plumage of these birds and its color is more intense in nestlings in poor condition in our study population. It has been proposed that developing birds in poor condition may increase their production of pheomelanin as a detoxifying strategy. Female nuthatches may thus prefer mating with males showing flank feathers of diminished color, as this could indicate that males experienced good conditions early in development, which can positively affect the fitness of future generations. Here we show results according with this prediction in a wild population of Eurasian nuthatches, as adult males with lighter chestnut feathers paired earlier in the season, while chestnut coloration had no effect on female mating success. Chestnut color expression was not affected by the body condition of birds, suggesting that females obtain information on the body condition in early life of their potential mates and not on their current body condition. This constitutes one of the few examples of females mating with males showing diminished traits and provides the only explanation so far by which this process can occur.

Materials and Methods

Mice and Genetic Crosses. Mutant sut and control C3H/HeSnJ mice were obtained from The Jackson Laboratory and subsequently bred in the animal facilities of Roswell Park Cancer Institute. All procedures (mouse protocols 125M) were approved by the Roswell Park Institutional Animal Care and Use Committee and adhered to the principles of the National Institutes of Health Guide for the Care and Use of Laboratory Animals.

Identification of the sut Gene. High-resolution genetic and physical maps of the sut critical region were generated with a backcross between homozygous sut/sut mice and PWK wild-type mice (subspecies Mus musculus musculus) as described in ref. 9 and based on the National Center for Biotechnology Information map viewer (build 32.1). Altogether, we typed 1,474 backcross progeny at 6 weeks of age for the sut pigment phenotype and for crossovers in the region surrounding sut by using the flanking microsatellites D3Mit3 (proximal) and D3Mit153 (distal).

We used 3′ RACE of mouse brain mRNA to find the alternative 3𠌮nd of the Slc7a11 mRNA in sut brain (GenBank accession no. <"type":"entrez-nucleotide","attrs":<"text":"AY766237","term_id":"59893995","term_text":"AY766237">> AY766237). Two alternative transcripts in C3H/HeSnJ brain cDNA with different poly(A) signals (GenBank accession no. <"type":"entrez-nucleotide","attrs":<"text":"AY766236","term_id":"59893993","term_text":"AY766236">> AY766236) were identified.

Expression Analysis. Total RNA was reverse transcribed as described in ref. 9. For Northern blot analysis of sut transcripts, poly(A)-mRNA (4 μg from brain and 2 μg from melanocytes) was isolated according to Promega PolyATract kit instructions, blotted, and hybridized with a transcript-specific 300-bp sut 32 P-radiolabeled probe (exons 9-11).

Cell Culture. The sut gene was transferred from the C3H/HeSnJ strain to the C57BL/6J strain by backcrossing for six generations. Melanocyte lines from sut/sut mutants were generated rapidly by deriving cell cultures carrying the Ink4a-Arf deletion to prevent cell senescence, as described in ref. 10. The C57BL/6J melan-a cell line (11) was used as wild-type control. Fibroblasts from skin of newborn C3H/HeSnJ and sut were established as described in ref. 12. Thioglycollate-elicited mouse peritoneal macrophages were isolated and cultured as described in ref. 13.

Cell numbers were measured in a Coulter Counter after trypsinization. Trypan blue assays indicated 㺕% viability of sut melanocytes after 1-4 days culture with β-mercaptoethanol (βME), whereas 㺐% were nonviable after 4 days culture without βME.

Rescue of sut Phenotype in Transgenic Mice. We injected bacterial artificial chromosome (BAC) RP23-2203 into pronuclei derived from hybrid (C3H/HeRos × C57BL/10 Rospd) F2 females. BAC-positive pups were mated with C3H/HeSnJ sut/sut mice to produce F1 progeny. BAC-positive F1 pups were backcrossed to sut/sut to produce F2 progeny. Each F2 pup was typed for coat color, presence of the BAC transgene, and presence of the deletion in the Slc7a11 gene.

Transport of [ 35 S]Cystine and [ 3 H]Leucine. Melanocytes from wild type (melan-a) and mutant (sut/sut) mice grown with βME were rinsed three times in warm PBSG [10 mM sodium phosphate/137 mM NaCl/3 mM KCl (pH 7.4), containing 0.9 mM CaCl2, 0.49 mM MgCl2୶H2O, and 5.6 mM glucose], and then incubated in uptake medium . The specificity of the cystine uptake system was determined in the presence of 2.5 mM unlabeled glutamic acid and arginine, separately.

Melanin Analysis. Eumelanin and pheomelanin were quantitatively analyzed (14) by HPLC based on the formation of pyrrole-2,3,5-tricarboxylic acid (PTCA) by permanganate oxidation of eumelanin and 4-amino-3-hydroxyphenylalanine (4-AHP) by hydriodic acid reductive hydrolysis of pheomelanin, respectively (1). These specific degradation products were determined by HPLC.

HPLC Analysis of Glutathione. Glutathione was analyzed by HPLC (15). To correct for the artifactual oxidation of glutathione, an aliquot of each sample was treated with 5% perchloric acid in the presence of 50 mM N-ethylmaleimide and analyzed in parallel.

Screening of HPS Patients. RNA was isolated from cultured fibroblasts of 15 HPS patients enrolled in a protocol approved by the National Institute of Child Health and Human Development and the National Human Genome Research Institute institutional review boards to study the clinical and molecular aspects of HPS. Mutation analysis for human SLC7A11 was performed on each patient's cDNA (transcribed from RNA by using Superscript RT-PCR, Invitrogen) in three overlapping fragments by using standard PCR and sequencing conditions.

PCR products spanning the 13 exons of SLC7A11 plus the adjacent intron and noncoding sequences were screened in genomic DNA of 17 other HPS patients who likewise lack mutations in the known human HPS genes plus one normal Caucasian control.

Dopa Histochemistry and Electron Microscopy. Dopa (3,4-dihydroxyphenylalanine) histochemistry was carried out by a method modified from that of Boissy et al. (16). Cells were fixed in 2.5% glutaraldehyde/2% paraformaldehyde in 0.2 M sodium cacodylate buffer (pH 7.2) for 1 h at room temperature and washed before incubation in l - or d -dopa (0.1% in cacodylate buffer) for two 2.5 h intervals at 37ଌ. ( d -dopa staining was used as a control and produced no stain.) The cells were washed as before and postfixed in 1% osmium tetroxide with 1.5% potassium ferrocyanide in cacodylate buffer for 1 h at room temperature. Three final washes were carried out before dehydration and embedding for sectioning.


A current model suggests that the eumelanin/pheomelanin ratio in mammalian pigmentation is controlled solely and indirectly by modulation of the activity of tyrosinase, the rate-limiting enzyme for melanin synthesis (22). This model postulates that at low tyrosinase concentrations dopaquinone reacts in melanosomes with sulfhydryls such as cysteine, yielding cysteinyl-dopa (1), and increased quantities of pheomelanin are produced. Although useful, this model for control of the eumelanin/pheomelanin ratio is incomplete. Our data demonstrate that the xCT transporter is a critical player in the control of pigmentation. However, unlike tyrosinase, it directly affects pheomelanin production with small increases in eumelanin in hair and cultured sut melanocytes. The loss of yellow pigment in sut mutants indicates that a critical rate of transport of cystine into melanocytes is essential for pheomelanin synthesis in vivo. The Slc7a11 gene directly affects this pheomelanin synthesis pathway. These results are consistent with biochemical evidence that cysteine is an important component of pheomelanin (1).

Several genes [melanocortin 1 receptor (Mc1r), pro-opiomelanocortin α (Pomc1), agouti (a), attractin (Atrn), and mahogunin (Mgrn1)] regulate the switching between eumelanin and pheomelanin synthesis in mouse hairshafts (23, 24). A knockout of the γ-glutamyl transpeptidase gene (25) and a mutation of the gray-lethal (ostm1) gene (26), which encodes a unique transmembrane protein (27), apparently affect pheomelanin. Loss of the former gene indirectly lowers tissue cysteine levels and produces a gray coat mutation of the latter causes clumping of pheomelanin granules and a gray coat. However, hair pheomelanin concentrations were not chemically ascertained in either case.

It is formally possible that the role of xCT, similarly to the agouti or melanocyte stimulating hormone proteins, is to signal pigment type switching. Alternatively, xCT may act in a permissive role to supply enough cystine so that pheomelanin synthesis can proceed. In this case, sut mutant melanocytes would be expected to divert dopaquinone that would otherwise have been converted to cysteinyl-dopa into the eumelanin branch. The 4-fold increase in eumelanin in hair of A y /a, sut/sut mutants is consistent with such a role. The permissive role likewise seems more plausible given the well documented role of xCT in cystine transport. However, additional experiments such as the analysis of expression of Slc7a11 mRNA during agouti banding are required to unequivocally distinguish these possible roles.

sut cells do not proliferate or survive under normal oxidizing culture conditions. Our data demonstrate that the xCT transporter maintains normal rates of delivery of cystine into cultured cells and thus is indispensable for cell growth and survival. Reduced cell survival probably results from loss of critical cellular defenses against reactive oxygen species by glutathione, which is substantially lost in sut melanocytes, particularly under oxidizing conditions in which cystine transport is greatly depressed. These results are consistent with studies showing that Slc7a11 expression is elevated in cells that require high glutathione synthesis for antioxidant defense (17). sut cells thus provide a model for oxidative stress-related diseases and their therapies. We speculate that alleles of SLC7A11 may regulate variation in human pigmentation (28, 29) as well as susceptibility to skin cancer and other harmful effects of UV radiation (2).

Whereas Slc7a11-deficient cells in culture rapidly expire because of oxidative stress, sut mice appear healthy. A likely explanation is that plasma, in contrast to typical culture media, contains significant levels of cysteine (30). The widely expressed alanine-serine-cysteine transporter (17) would be expected to transport plasma cysteine intracellularly at levels sufficient for viability of sut tissues. Nevertheless, cells such as melanocytes, with attendant high cysteine requirements, manifest a mutant phenotype in sut mice.

The oxidizing environment generated by culturing Slc7a11-negative sut melanocytes in the absence of βME causes abnormal trafficking of the critical melanosomal enzyme tyrosinase to a perinuclear (perhaps trans-Golgi) location, although this abnormality does not alter production of eumelanin pigment. Abnormal trafficking of tyrosinase is apparently a general feature of HPS, being observed in the reduced-pigmentation HPS mouse mutant (10) and in melanocytes of HPS-1, HPS-2, and HPS-3 patients (31, 32). Whether Slc7a11 directly or indirectly regulates trafficking of tyrosinase and other important components of lysosome-related organelles requires further investigation.

Why are there redheads? Birds might hold the clues

Red coloration -- historically seen as costly in vertebrates -- might represent some physiological benefit after all, according to research published in the journal Physiological and Biochemical Zoology.

Pheomelanin, which is responsible for red hair and freckles in humans and orange and chestnut coloration in other animals, is known to increase the damage to skin cells and melanoma risk when present in large amounts. Furthermore, its creation involves the consumption of glutathione, a beneficial antioxidant.

In an attempt to unearth the factors favoring the evolution of pheomelanin in spite of its costs, Ismael Galván and Anders P. Møller of the University of Paris-Sud examined the survival from one breeding season to the next of a wild European population of barn swallows, as well as the annual survival rates of 58 species of American birds.

A recent hypothesis claims that the consumption of cysteine (a component of glutathione) that occurs when pheomelanin is produced can be beneficial under conditions of low stress. Cysteine, which is mainly acquired through diet, can be toxic at high levels, so the production of pheomelanin may help to sequester excess quantities of this amino acid.

Galván and Møller measured birds' blood levels of uric acid and analyzed the coloration of their chestnut throat feathers (an indication of pheomelanin content). When they compared birds that had similar uric acid levels (and therefore similar capacities to excrete excess amino acids), they found that both the European barn swallows and the American birds with larger amounts of pheomelanin in their feathers survived better.

This study is the first to propose that the costs/benefits of pheomelanin may depend on prevailing environmental conditions, and its results suggest that the production of this pigment may even be beneficial in some circumstances. Given that all higher vertebrates, including humans, present pheomelanin in skin, pelage, and plumage, Galván and Møller's findings increase the scant current knowledge on the physiological consequences of pheomelanin and open new avenues for research that will help us understand the evolution of pigmentation.


MELANIN – the pigment

Melanin is a pigment that produces different colors in skin and hair. It is a pigment that protects you .

By conferring color to skin, melanin protects skin from damaging UV rays. It functions like an antioxidant by quenching free radicals. In fact, it is an efficient antioxidant .

There are 2 kinds of melanin:

  1. Eumelanin – yellow to brown to very dark brown (almost black) color seen in brown-black hair
  2. Pheomelanin – red-yellow color seen in red hair

The amount of each type of melanin partly determines your skin and hair color.

MELANOCYTES – produce the pigment

Melanin is produced by special cells called MELANOCYTES located in the basal layer of the epidermis.

Melanin production begins when there is a trigger, such as UV radiation . This is why you tan and get sun spots from being in the sun.

Melanocytes perform several important functions:

  • scatter UV light
  • absorb heat
  • neutralize Reactive Oxygen Species
  • protect DNA from UV damage
  • protect cell membranes from oxidation

These melanocytes have octopus-like tentacles (dendrites) that carry melanin to nearby skin cells (keratinocytes) when they are needed (i.e. when skin is exposed to the sun’s damaging UV rays).

The melanin that is deposited in the skin cells serves to protect the DNA .

If your skin tans , it is a sign that you already have DNA damage. This is why there is no such thing as safe tanning. By definition, a tan is a sign of skin damage.

When you exfoliate or get ablative procedures done (lasers), the pigment that comes off first is the pigment in the stratum corneum . Pigment can still re-appear later because it is produced in the layers below and takes a long time to migrate to the outermost layer of skin.

MELANOSOMES – carry the pigment

Melanin granules are contained in organelles called MELANOSOMES . The melanosomes are like parcels. These melanosome parcels move along the dendrites into nearby keratinocytes where they can continue to migrate upward through the epidermis.

Biological productivity

Assorted References

(Productivity is often measured by an increase in biomass, a term used to refer to the weight of all living organisms in an area. Biomass is reported in grams or metric tons.)

…called the primary or secondary productivity (the former for plants, the latter for animals), is usually measured in units of energy, such as gram calories or kilojoules per square metre per year. Measures of weight—e.g., tons of carbon per square kilometre per year or gigatons of carbon per year—are also…



The high level of plant production in estuaries supports a correspondingly high level of production of invertebrate animals and fish. Estuaries often contain beds of shellfish such as mussels and oysters and large populations of shrimps and crabs. Fish such as plaice and flounders

Central to all biological activity within inland aquatic ecosystems is biological productivity or aquatic production. This involves two main processes: (1) primary production, in which living organisms form energy-rich organic material (biomass) from energy-poor inorganic materials in the environment through photosynthesis, and (2)…

Primary productivity is the rate at which energy is converted by photosynthetic and chemosynthetic autotrophs to organic substances. The total amount of productivity in a region or system is gross primary productivity. A certain amount of organic material is used to sustain the…


In the highly stressful desert environment, productivity is generally very low however, it is also highly variable from time to time and from place to place. (For a full discussion of productivity, see biosphere: Resources of the biosphere.)

Because of its importance for grazing and other grassland agricultural production, grassland productivity has been extensively investigated using various methods. However, most studies have focused only on aboveground productivity, ignoring the important subterranean component, which can be much more substantial—as much as 10…

As stressful habitats for plants, mountain lands are not very productive environments. The biomass (dry weight of organic matter in an area) of the alpine vegetation on high temperate mountains, however, may be greater than it first appears because more than 10 times…

Savannas have relatively high levels of net primary productivity compared with the actual biomass (dry mass of organic matter) of the vegetation at any one time. (For a full discussion of productivity, see biosphere: The photosynthetic process.) Most of this productivity is concentrated…

Scrublands typically grow under conditions of high environmental stress. The typical climatic environment experienced by scrublands includes long periods of hot, dry weather in which lack of moisture is a limiting factor for plant growth. Furthermore, soil nutrient levels typically are very low.…

The total aboveground biomass (dry weight of organic matter in an area) for temperate deciduous forests is typically 150 to 300 metric tons per hectare values for temperate broad-leaved forests are generally higher, and those for sclerophyllous forests are lower. The subterranean component…

Of all vegetation types, tropical rainforests grow in climatic conditions that are least limiting to plant growth. It is to be expected that the growth and productivity (total amount of organic matter produced per unit area per unit time) of tropical rainforests would…

An important measure of natural ecosystems is the biological production of its plants and animals—that is, the total amount of biomass produced by living organisms within a given area in a specific period of time. In polar regions the greatest biological production occurs…

What is eumelanin and pheomelanin in hair?

Click to see complete answer. Herein, what is the difference between eumelanin and pheomelanin?

Eumelanin is a dark pigment that predominates in black and brunette hair. There are two different types of eumelanin (brown eumelanin and black eumelanin). Pheomelanin is a lighter pigment found in red hair, and is concentrated in the redder areas of the skin such as the lips.

Secondly, how can I increase melanin in my hair? Eating vitamin C&ndashrich foods like citrus, berries, and leafy green vegetables may optimize melanin production. Taking a vitamin C supplement may help as well. Shop for vitamin C.

Hereof, what causes Pheomelanin?

Certain genetic variations are most common in people with red hair, fair skin, freckles, and an increased sensitivity to sun exposure. These MC1R polymorphisms reduce the ability of the melanocortin 1 receptor to stimulate eumelanin production, causing melanocytes to make mostly pheomelanin.

What are the 2 types of melanin?

There are three basic types of melanin: eumelanin, pheomelanin, and neuromelanin. The most common type is eumelanin, of which there are two types&mdash brown eumelanin and black eumelanin.

MC1R and Its Role in Skin Cancer

The melanocortin-1 receptor (MC1R) is a G-protein coupled 7-membrane spanning receptor (GPCR) that was originally described on cells of melanocytic origin, but is also present on keratinocytes, fibroblasts and most immune cells, suggesting that it can influence innate and adaptive immunity 81, 82 . MC1R function is important in regulating the amount of eumelanin pigment produced after UVR, and it is activated by a class of peptide hormones called melanocortins (MC), derivatives of proopiomelanocortins (POMCs) produced in the pituitary gland. Among various MCs, α-MSH is responsible for pigmentation in humans and coat color in mice 83, 84 . MC1R belongs to a five-member subfamily of GPCRs that mediate the physiologic actions of MCs by activating G-proteins that, in turn, activate the cyclic AMP signaling pathway. The human and mouse MC1R genes were cloned in 1992 85, 86 . The cloning of the other mammalian MC1Rs shows that this gene is highly conserved in mammals. As shown in Fig. S1, an alignment of MC1R protein sequences from different organisms are highly similar between the different mammalian species. Bird or reptile sequences have lower identity, but conservation at the arginine and cysteine residues indicate their importance in MC1R function (Figs. 5 and S1). Indeed, mutations at these highly conserved residues lead to MC1R inactivation, and are found in red-headed individuals (Fig. 6). Because MC1R is resistant to crystal formation, its protein structure has been deduced using information from modeling of its secondary and tertiary structures in comparison to bacteriorhodopsin, the prototype molecule for the class A subfamily of GPCRs, of which MC1R is a member 87-91 . MC1R has a typical seven transmembrane structure, with an N-terminus that extends extracellularly, a C-terminus that is intracellularly located, with a series of intracellular and extracellular loops in between (Fig. 6).

The MC1R gene has a high number of allelic polymorphisms, mainly in Caucasian populations 92 . Recently, it has been documented that there are 57 nonsynonymous and 25 synonymous polymorphisms in different populations 93 . The N-terminus consists of many residues that are glycosylated. There are also cysteine residues, which are highly conserved in all MC1R alleles, because, when mutated to glycine or alanine leads to receptor inactivation 94, 95 . Among the three extracellular loops, the third loop harbors a number of proline and the cysteine residues that are conserved and along with residues from loop 2 are critical in ligand binding 91, 94 . Loop 1 has many residues that are prone to mutations. There are four intracellular loops, with potential sites for binding of G-proteins and motifs for phosphorylation. Mutations in these loops can occur at key positions that lead to loss of function. Other polymorphic variants in transmembrane regions also result in loss of function. These include Arg142His, Arg151Cys, Arg160Trp and Asp294His substitutions, which are strongly associated with red hair phenotype, poor tanning ability, and, significantly, associated with melanoma and possibly nonmelanoma skin cancer 96-100 . A number of alleles, such as Val60Leu, Val92Met and Arg163Gln substitutions, are thought to have lower penetrance for red hair phenotype but are vital for MC1R function. The cytosolic tail is short and has a cysteine residue that is a potential site for acylation. Information covering MC1R structure and its associated mutations is presented in greater detail, reviewed by Garcia-Borron et al. 91 .

MC1R and immune system

Some of the immune-regulating properties of eu- and pheo-melanin were noted above. As MC1R signaling is central to eu- and pheo-melanin regulation, it is important to determine whether MC1R induces its effects independent of melanin production. Using animal models, it has been shown that MC1R and other MCRs like MC3R and MC5R can influence inflammatory processes and the presence of MC1R on most immune cells suggests that it can affect both adaptive and innate responses 101-103 . Furthermore, α-MSH, originally thought to be produced solely by the pituitary gland, is also secreted by most immune cells 81 . Although α-MSH exerts its immune modulation and anti-inflammatory activity through activation of MC1R, the receptor and ligand are not exclusive to each other. Other ligands like ACTH can also stimulate MC1R, whereas α-MSH can activate other MCRs. α-MSH exerts a wide range of activities that includes anti-inflammatory effects and immunomodulation through MC1R signaling on macrophages and neutrophils 2, 104 . MC1R expression can be induced on most immune cells. Its expression level can be altered on monocytes following lipopolysaccharide (LPS) 105 . Stimulation of MC1R on endothelial cells leads to downregulation of adhesion molecules: E-selectin, vascular cell adhesion molecule (VCAM) and intercellular adhesion molecule (ICAM) 106 . Further MC1R stimulation can also reduce TNF-α production in endothelial cells 107 and production of cytokines such as IL-1, TNF-α and IL-6 and nitric oxide in monocytes 81, 108, 109 . This decrease in cytokine production is reportedly due to inhibition of NFκB activation 104, 110-112 and IκBα degradation 113 . Thus, the reduced inflammatory responses in tissues may be partly due to direct reduction of inflammatory cytokines and downregulation of adhesion molecules on endothelial cells, which leads to a reduction in inflammatory cell influx (Fig. 4). Thus, the anti-inflammatory activities of MC1R signaling during UVR might play an important role in preventing UVR-induced carcinogenesis. It is noteworthy that mice lacking the MC1R have a normal immune system, but how they respond to external stressors needs further investigation 114, 115 .

α-MSH/MC1R signaling induces tolerogenic dendritic cells that were shown to expand regulatory T cells (Tregs) in vitro, as well as in vivo 116 . The α-MSH-stimulated DCs induced Tregs that were functional, as they inhibited the proliferation and cytokine secretion of T-helper-17 (Th17) cells from individuals with psoriasis. Furthermore, α-MSH has been shown to downregulate CD86, a major T-cell costimulatory molecule on monocytes 105 . Peripheral blood monocytes stimulated with α-MSH increase IL-10 transcription and secretion 117 . IL-10 is a highly immunosuppressive cytokine and an excellent inducer of regulatory T cells 118 , which are often associated with tumor-induced immune suppression. A minority of studies report that IL-10 possesses antitumor properties under some conditions 119 . Taking these findings together, it can be hypothesized that MC1R has an important role in supporting an immunosuppressive environment which may facilitate UV-induced tumorigenesis.

On the other hand, stimulation of MC1R on certain immune cells can lead to a reduction in tumor development in mouse model systems. Loser et al. showed that when α-MSH treated CD8+T cells were transferred into mice, they became resistant to developing allergic contact hypersensitivity responses, but at the same time, maintained melanoma-specific CTL activity, as demonstrated by the expression of CTL-related genes and specific cytolytic activity in vitro and in vivo 102 . Thus, it can be argued that MC1R maintains a balance of controlled inflammation that facilitates the maintenance of a tumor free environment.

How to increase pheomelanin production? - Biology

a Department of Evolutionary Ecology, Doñana Biological Station – CSIC, 41092 Sevilla, Spain
E-mail: [email protected]

b Laboratory of Non-Destructive Analytical Techniques, National Museum of Natural Sciences – CSIC, 28006 Madrid, Spain

c Department of Animal Genetic Improvement, Institute for Agricultural and Food Research and Technology (INIA), 28040 Madrid, Spain


Vibrations in covalent bonds affect electron delocalization within molecules, as reported in polymers. If synthesized by living cells, the electron delocalization of polymers affects the stabilization of cellular free radicals, but biomolecular vibration has never been considered a potential source of cytotoxicity. Here we show that the vibrational characteristics of natural pheomelanin and eumelanin contribute to feather color expression in four poultry breeds with different melanin-based pigmentation patterns, but only the vibrational characteristics of pheomelanin are related to the production of reactive oxygen species (ROS) in the mitochondria of melanocytes and to systemic levels of cellular oxidative stress and damage. This association may be explained by the close physical contact existing between mitochondria and melanosomes, and reveals an unprecedented factor affecting the viability of organisms through their pigmentation. These findings open a new avenue for understanding the mechanism linking pheomelanin synthesis to human melanoma risk.

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