Friday, September 21, 2012

Skin Lightening: Of Natural Derivation

Skin lightening, de pigmentation of the skin is of growing interest amongst the aging population as well as those choosing to lighten their skin for cosmetic or cultural reasons. In some countries there remains a stigma attached if a person is known to be actively lightening their skin. Skin lightening / whitening may utilize ingredients with various associated hazards when used inappropriately, while others have a less toxic effect. Skin lightening, naturally has been explored to varying degrees of success. Many choose to DIY skin lightening lotions, body wash, creams, due to the cost as well as the fear of steroids potentially being included. Lemon juice, lime juice,  citric acid and various other components are used as a simple and moderately effective methods to lighten the skin. People around the globe of many ethnicity are looking to lighten skin for personal reasons. Hyper pigmentation due to UV exposure over a life time has become a common theme. Do It Yourself methods meet with varying degrees of success. Not all skin lightening products are created equal, nor do they work along the same mechanisms. Some are next to useless. To whiten or bleach the skin is not a simple matter, nor is it permanent. Effective treatment requires several months before the effects are noticed and are quickly lost due to sun exposure. Maintaining a consistent regime will play an important role in the efficacy of any treatment, whether you make it yourself or purchase from a drugstore.

To beautify the skin, i.e. reduce evidence of age spots, darkened areas of pigmentation, is of great concern to many.  An even skin tone is considered by most cultures to be beautiful. How to safely achieve even skin tone for sun damaged skin is more difficult. Skin beauty is a personal journey and the stigma attached to skin lightening is often not considered. The experts on what constitute beautiful skin are the ones in the mirror's reflection. Healthy skin, is generally considered to be even in tone, of smooth texture, unlined and without acne. Many of the natural skin lightening ingredients also contain cross over action in other mechanism due to the complexity of the chemical composition inherent to several of the known plant extract lighteners. While they are effective at skin lightening, they remain effective antioxidants. Whether dark skinned or light skinned,  even skin tone remains a desirable aspect of beauty. While many wish to lighten their skin tone, others are trying to go darker. That which constitutes beauty, lies in the eyes of the beholder, even if that remains the self.

As the end user of any lotion, milk , serum, cream, it is the individual experience that determines the efficacy or not thereof. DIY / homemade lotions, bath body wash and serums are made with the goal to lighten the skin, in  hopes that pigment will disappear or old age spots likewise. Can this be done safely and without irritation or allergic reactions? Drugstores and big name labels sell lotions that claim to lighten the skin, however the concentrations of the active components are unknown. They may also be in a base that causes allergic reaction,  where as the active itself may not. Some actives are inherently unstable, and by the time they reach the consumer, they are of little use. Safest and most effective are not necessarily mutually exclusive when it comes to skin lightening. Safest generally requires longer treatment time.

To improve the efficacy of a skin whitening treatment or regime, it is prudent not to play games with chemicals that are proven to cause permanent damage when it can readily be avoided. Several plant extracts contain effective chemicals for lightening pigmentation and the research has greatly refined the understanding of the mechanisms of  action over the years. It remains prudent to keep in mind that not each individual will have the same success,. It would be nice to guarantee the efficacy of a product however far too many variables come into play. The type of oil used to make a homemade/ DIY lotion due to the palmitic acid content can undo the positive effect of the lightening chemical component/ extract. As the consumer knowledge base continues to increase, producers are forced to meet the demand. Unfortunately due to restrictions in various jurisdictions for health and safety concerns, truly effective formulas are not necessarily readily available.

Understanding  the pigmentation pathway as currently known is useful prior to examining the various skin-lightening compounds and the assosciated mechanisms of action. Skin color is determined by both the type and quantity of melanin synthesized by the melanocyte and its distribution pattern in the epidermis. The formation of melanin  is through a series of oxidative reactions involving the amino acid tyrosine and the enzyme tyrosinase.

Most critical is the first reaction as the  reaction sequence that follows  proceeds spontaneously at physiological pH. At this point in the sequence, tyrosinase converts tyrosine to dihydroxyphenylalanine (DOPA) and subsequently to dopaquinone. Thereafter, dopaquinone is converted to dopachrome through auto-oxidation, and, finally, to dihydroxyindole or dihydroxyindole-2-carboxylic acid (DHICA) to form eumelanin (black-brown pigment= darken the skin). The latter reaction occurs in the presence of dopachrome tautomerase and DHICA oxidase. In the presence of cysteine or glutathione, dopaquinone is converted to cysteinyl DOPA or glutathione DOPA. The latter results in the formation of pheomelanin, a yellow-red pigment. ( influences skin tone )


Tyrosinase regulates  melanin synthesis in melanocytic cells. It is a membrane-bound copper containing glycoprotein, and the critical rate-limiting enzyme of melanin production. Tyrosinase is produced only by melanocytic cells, post its synthesis it is further processed in the ER and Golgi.  After processing it is transported to melanosomes, where the pigment is synthesized and deposited. Melanosomes are transferred from melanocytes to neighboring keratinocytes and are distributed in the skin and hair to produce visible color. An excess of melanin or abnormal distribution can cause irregular pigementation and hyperpigmentation of the skin. Developing effective therapies to treat disorders of pigementation, disruption of tyrosinase activity is the usual target. Several approaches exist to decreases tyrosinase activity i.e. competitive or non-competitive inhibition of tyrosinase catalytic activity,   disruption of tyrosinase maturation or by reduce its stability. Manipulation of tyrosinase levels include modulating of tyrosinase messenger RNA (mRNA) transcription and its post-transcriptional stability or reducing its potential for synthesis at the gene expression level.

Before treating hyperigmentation the etiology must first be elucidated. It is not always clear as there are many factors that influence hyperpigmentation: 1) photo sensitizing agents, 2) hormone imbalance, 3) UV exposure, 4) Systemic disease, 5) drug interactions. etc.

A variety of topical treatments have been developed and some with exceptional effect. The current Gold Standard is the use of Hydroquinone (HQ) . HQ is considered to be one of the most effective in vivo and in vitro inhbitors of melanogensis which causes a reversible inhibition by affecting both DNA and RNA synthesis. The unfortunate aspect is that while it is effective at inhibiting melanocytes it remains cytotoxic to the surrounding cellular structures and leads to degeneration of both collagen and elastin fibers. Inappropriate usage may lead to darkening of the skin. Care must be taken when using potent lightening agents.

Tyrosinase Inhibitors:
There are a variety of effective inhibitors however they are not true inhibitors of tryosinase, rather they act to interfere with the production of melanin. L ascorbic acid is one such molecule. It acts to  to reduce  o-dopaquinone to dopa, avoiding dopachrome and melanin formation.  AA2G is also shown to be particularly effective for those that cannot tolerate the low pH requirement of LAA.

Phenolic compounds are another broad category of which many have been isolated and found to be effective. These enzyme substrates show good affinity for the binding site on tyrosinase and result in a reduction in the formation of dopachrome. Some act as cheltors of copper which also acts to inhibit enzymatic activity via destabilization of tyrosinase.

Acids or bases also act as inactivators of tyrosinase. These act to denature the enzyme, leaving it non functional and as such, inhibit activity.

Suicide substrates are another class of inhibitors and more correctly true inhibitors. These act to bind tyrosinase  irreversibly. These inhibitors are catalyzed by tyrosinase forming covalent bonds and inducing the enzyme catalyzing  "suicide reaction."

True inhibitors are of four types. 1) competitive inhibitors, 2) noncompetitive inhibitors, 3) mixed  (competitive/non-competitive) inhibitors, and 4) non-competitive inhibitors.

1. Competitive inhibitor: a substance that combines with a free enzyme in a manner that prevents substrate binding. That is, the inhibitor and the substrate are mutually exclusive, often because of true competition for the same site.

2. Non competitive inhibitors: can bind only to the enzyme-substrate complex.

3. Mixed  (Competitive/ Non competitive) inhibitors: can bind  with a free enzyme and with the enzyme-substrate complex.

4. Non-competitive inhibitors: bind to a free enzyme and an enzyme-substrate complex with the same equilibrium constant.

The science of skin lightening/ depigmentation is growing as each year more compounds are isolated and their mechanism of effect studied. As  knowledge of melanocyte biology and  underlying processes of melanin synthesis are understood, new approaches  to the treatment of skin hyperpigmentation become available. Not only is tyrosinase inhibition of catalytic activity an option, other alternatives include: 1) inhibition of tyrosinase mRNA transcription, 2) aberration of tyrosinase glycosylation and maturation,  3) acceleration of tyrosinase degradation, 4) interference with melanosome maturation and transfer, 5) inhibition of inflammation-induced melanogenic response, and 6) acceleration of skin turnover.

Kojic acid is one of the most commonly used depigmenting agents and a natural agent with few side effects. It is well tolerated by most but skin sensitivity can occur in some individuals and the potential for irritation increase with the concentration.  Kojic acid is a fungal metabolite  produced by many species of Aspergillus, Acetobacter, and Penicillium. It is  know  to act as a competitive and reversible inhibitor of tyrosinase which catalyzes the conversion of tyrosine  to melanin via 3,4-dihydroxyphenylalanine and dopaquinone. Kojic acid remains the standard against which new de- pigementing agents are measured. As it is a completely natural product its popularity has grown, albeit it is not the most effective.

Arbutin (ß) ( Uva Ursi and bearberry extract, hydroquinone-beta-D-glucopyranoside) is a botanical extract  in which the active component hydrolyzes readily into hydroquinone.  Researchers shows it inhibits the oxidation of L-DOPA catalysed by mushroom tyrosinase and is effective in the topical treatment of various cutaneous hyperpigmentations characterized by hyperactive melanocyte function. A another study indicated that arbutin inhibits melanin synthesis by inhibition of tyrosinase activity apparently  due to the inhibition of melanosomal tyrosinase activity rather than the suppression of this enzyme’s synthesis and expression. Arbutin itself is oxidized  at an extremely slow rate, but accelerates when dihydroxyphenylalanine (L-DOPA) becomes available as  co factor.

Morus alba, Mulberry extract is a composite of polyphenols which have shown to have 32 fold the inhibitory activity of Kojic acid. It acts non-competitively on both monophenolase and diphenolase activity of mushroom tyrosinase.  The inhibtion mechanism of the compound directly inhibits enzyme activity but does not affect gene expression. Aside from its more potent effect than Kojic acid for melanin inhibition, Morus alba extract has also shown superoxide scavenging activity.

Licorice extract, extracts from the roots and seeds of Glycyrrhiza species are commonly used in Asia as a lightening compound. Glabridin and glabrene are the two components of Licorice extract that act in a non competitive manner to inhibit melanogenesis. Glabridine has 15 times the activity of kojic acid and exhibited higher depigmenting activity than  arbutin. Glycyrrhizic acid  another compound within Morus alba is renowned for it's anti inflammatory and anti oxidant effects. 

Raspberry ketone from Rheum officinale, one of the major aromatic compounds of raspberry, is widely used in perfumery,  cosmetics, and as a flavoring agent in foodstuffs has shown strong inhibitory effects. Currently it is marketed primarily as a weight loss aid, however it is also known for anti-androgenic activity and anti inflammatory activity. It has also been shown to be an extremely potent tyrosinase inhibitor on par with hydroquinone. The exact mechanism is not completely understood however it is suggested that RK inhibits melanogenesis through a post-transcriptional regulation of tyrosinase gene expression, which results in down regulation of both cellular tyrosinase activity and the amount of tyrosinase protein, while the level of tyrosinase mRNA transcription is not affected. Rk hold particular promise as it is a safe compound and effective on mammalian tyrosinase. RK is also multifunctional as in other research it has shown to reduce the signs of dermal laxity and exhibits some promise in hair loss reduction.

Each compound has quantifiable  capacity to affect melanogenesis via specific mechanisms. None are permanent. The complete eradication of pigment  from the skin remains dangerous. Melanin is the first line of defense from the ravages of UV damage. When using lightening compounds one must also use a high SPF sunscreen. Sensible precautions must be employed. Endangering one's  health for the sake of change of skin color is not worth the long term side effects. When using any homemade creams or lotions, test for sensitivity and observe the reactions. Adjust accordingly or discontinue if necessary.

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