After roundly being berated for writing Ph.D. style blogs, I try very hard not to write scientific/ jargon-filled blogs. Unfortunately, this is one such blog. Sorry. I cannot conceivably write about skin lightening products without this blog.
In my previous blog, What gives our skin its colour? I briefly wrote about:
– How Melanin determines skin colour (specifically Eumelanin) AND
– Eumelanin has a photo-protective effect on skin and is prevalent in darker-skinned individuals.
One of the consequences of the disparity in skin pigments between dark and light-skinned individuals is that the risk of skin-cancer in lighter-skinned individuals is 30-40 fold higher than in darker skin. (Del Marmol V et al 1996).
Today’s blog is how melanin is formed or Melanogenesis.
Why write this techie blog?
The effects of melanin interference include brighter skin, whiter skin, de-tanning, fading dark spots including pigmentation, dark circles, melasma and so on. You cannot understand skin lightening and how these effects are achieved if you don’t understand how melanin is formed.
PART ONE: 50,000,000 feet view of Melanogenesis
- Our skin contains Melanocytes, which in turn contain Melanosomes, which produce melanin. As melanosomes move around they dissipate melanin pigment (and therefore colour)
- The building block of melanin is L-Tyrosine, an amino acid that goes through a bunch of steps to get to melanin
- TYROSINASE is an enzyme that is critical to the formation of both Eumelanin AND pheomelanin.
- Copper is essential to the normal functioning of Tyrosinase.
That’s as technical as we are going to get today…if you take anything away from today, let it be: TYROSINASE is the rate limiting Copper containing enzyme vital to melanin synthesis.
| An increase in Tyrosinase activity increases Melanin production, which darkens the skin. |
| A decrease in Tyrosinase activity decreases Melanin production, which lightens skin. |
****THIS IS YOUR OFFICIAL GEEK ALERT. STOP READING IF YOU HAVE NO INTEREST IN WHAT DOPACHROME IS OR TRANSCRIPTION FACTORS ARE****
Today we are going to be discussing MELANOGENESIS, which is the synthesis of melanin.
The preliminary step to Melanogenesis is the conversion of L-Phenylalanine to L-Tyrosine via intracellular Phenylalanine Hydroxylase. Phenylalanine is actively transported through to the Melanosome membrane.
The site of melanogenesis is Melanocytes and within Melanocytes, Melanin is produced within organelles called Melanosomes.
For skin, there are 2 types of melanin we are interested in: Eumelanin and Pheomelanin
L-Tyrosine is the absolute basic building block for melanin. The rate limiting enzyme Tyrosinase is responsible for converting L-Tyrosine to L-DOPA (or Dihyroxyphenylalanine) via hydroxylation (i.e., adding an -OH group) and then the oxidation of DOPA to DOPAquinone.
At this point the formation of Eumelanin and Pheomelanin diverges.
Formation of Pheomelanin
Pheomelanin production is dependent on the presence of Cysteine. No Cysteine, then no Pheomelanin. Cysteine reacts with DOPAquinone to form Cysteinyl DOPA, which is ultimately converted to Pheomelanin.
In the absence of Cytseine, DOPAquinone is spontaneously converted to DOPAchrome.
Formation of Eumelanin
TRPY-2 converts DOPAchrome to DHICA (5,6-Dihydroxyindole-2-Carboxylinc Acid), which is then oxidized to Eumelanin. The oxidation of DHICA to Eumelanin is thought to be catalysed by TRPY-1.
In the absence of TRPY-2, DHICA spontaneously becomes DHI, which then ultimately forms Eumelanin as well.
Run Tyrosinase enzyme function by me again…
I cannot stress enough how important Tyrosinase is because most skin lighteners focus in some shape or form on the inhibition or reduction in activity of Tyrosinase.
Tyrosinase is the rate limiting enzyme that is a copper containing glycoprotein that is absolutely essential to melanogenesis. Copper is essential to activity of Tyrosinase.
Note that Histidine (an alpha amino acid) residues are present in the inner catalytic portion of the Tyrosinase enzyme and bind Copper ions that are essential for Tyrosinase activity.
Tyrosinase is activated by excessive exposure to UV radiation. It is also indirectly activated by TH1.
What is the role of TH1?
TH1 or Tyrosine Hydroxylane Isoenzyme 1 (TH1) also indirectly activates Tyrosinase as its been shown to be present in Melanosomes and catalyse to L-DOPA synthesis. In turn L-DOPA can also be a co-factor for Tyrosinase.
What does rate limiting mean?
In every metabolic pathway there is at least one reaction that is far from equilibrium because of the relatively low activity of the enzyme involved. The rate of the reaction is not limited because of the lack of substrate availability – its limited because of the activity of the enzyme. Hence, rate limiting.
What are TRYP-1, TRYP-2?
Tyrosinase Related Protein 1 (TRYP-1) and Tyrosinase Related Protein 2 (TRYP-2) are structurally related to the enzyme Tyrosinase
The reside within melanosomes.
It has been suggested that a TRYP-1 increase, increases Eumelanin to Pheomelanin ratio.
Also TRYP-1 and TRYP-2 have been demonstrated to increase TYROSINASE stability.
The full extent of their role in Melanogenesis has not as yet been figured out.
What is Cysteine?
Cysteine is a non-essential amino acid. Its one of the few amino acids that contains Sulphur. Cysteine is a building block of Glutathione.
What is MITF transcription factor in all of this?
MITF has been shown to be a key transcription factor for a protein that is important for melanosome transport. This protein is Rab 27A.
On transcription activity being triggered, MITF efficiently activates the melanogenesis enzyme genes such as Tyrosinase and TRYP-1 and TRYP-2 in cultured cells.
MITF plays an essential role in melanin synthesis and melanosome formation and transport.
Role of Alpha-MSH
Paracrine Melanogenic stimulators include Alpha-MSH, which have in vivo been demonstrated to increase skin pigmentation especially in sun-exposed areas.
What are the most important factors other than inheritance that affect skin pigmentation?
The answer is Ultra Violet Exposure. Ultra Violet Radiation triggers the following which causes skin darkening:
1. Oxidation and polymerization of Melanin
2. Redistribution of melanosomes
3. Activation of MITF leading to increased melanin content
4. Increase in the expression of Alpha-MSH, a melanocyte stimulating hormone, that increases melanin content
5. Transfer of melanin from the lower to upper epidermis.
What do skin lighteners do?
- Inhibit the enzyme Tyrosinase which is essential to the formation of melanin
- MITF inhibition, which prevents Tyrosinase being triggered
- Down regulates MC1R activity
- Interferes with the transfer and maturation of melanosome, resulting in less melanin
- Melanocyte loss, via exfoliation
Abbreviations
α-MSH: melanocyte-stimulating hormone
DOPA: Dihyroxyphenylalanine
DHI: dihydroxyindole
DHICA: dihydroxyindole-2-carboxylic acid
MITF: microphthalmia-associated transcription factor
MCR 1: melanocortin receptor 1
TRYP: Tyrosinase Related Protein
Sources and uses
Absolutely everything I have written above is in some shape or form attributable to the authors below. I cannot add hyperlinks as this causes my blog to keep crashing.
Cichorek M et al, Skin melanocytes: biology and development, Postępy Dermatologii i Alergologii 30 XXX; 2013/1 Review Paper
Yamaguchi Y, The Regulation of Skin Pigmentation Invited JBC MiniReview
Brenner M et al The Protective Role of Melanin Against UV Damage in Human Skin Photochemistry and Photobiology, 2008, 84: 539–549
Parvez S et al Survey and Mechanism of Skin Depigmenting and Lightening Agents Phytother. Res. 20, 921–934 (2006)
Sonthalia S et al, Glutathione as a skin whitening agent: Facts, myths, evidence and controversies Indian Journal of Dermatology Venereology and Leprology · March 2016
US Patent 5,773,014, June 30, 1998, Compositions and Methods For Inhibiting the Formation of Unwanted Skin Pigmentation
Couteau C et al Overview of Skin Whitening Agents: Drugs and Cosmetic Products Cosmetics 2016, 3, 27;
Kamakshi R Fairness via formulations: A review of cosmetic skin-lightening ingredients J. Cosmet. Sci., 63, 43–54 ( January/February 2012)
Te-Sheng Chang An Updated Review of Tyrosinase Inhibitors Int. J. Mol. Sci. 2009, 10, 2440-2475 Natural Melanogenesis Inhibitors Acting Through the Down-Regulation of Tyrosinase Activity Materials 2012, 5, 1661-1685;
Lukman M et al Antityrosinase effect of botanicals: A review of medicinal plants cosmetic J. Chem. Pharm. Res., 2015, 7(5):716-722
Sarkar R et al Cosmeceuticals for Hyperpigmentation: What is Available? Journal of Cutaneous and Aesthetic Surgery – Jan-Mar 2013, Volume 6, Issue 1
Ebanks J Mechanisms Regulating Skin Pigmentation: The Rise and Fall of Complexion Coloration Int. J. Mol. Sci. 2009, 10, 4066-4087;
Gillbro J The melanogenesis and mechanisms of skin-lightening agents – existing and new approaches International Journal of Cosmetic Science, 2011, 33, 210–221