Skin Lightening and Skin Bleaching: The Difference, Part 2

We continue our discussion of skin lightening and skin bleaching, the difference between the two. We begin by focusing our attention on the actual chemical agents found in products, perhaps some of them you are using or have used to understand what they do.  Some lighten skin.  Some bleach skin.  Often, the chemical structure dictates 1) whether the compound has the capacity to lighten skin, by controlling the rate that Tyrosinase produces the precursor to melanin or 2) or whether the compound has the capacity to bleach skin, perhaps by completely rendering Tyrosinase inactive or by inactivating or killing the melanin-producing cell.

Let’s consider the classes of Tyrosinase inhibitors:

 

SKIN LIGHTENING AGENTS

1. PHENOL DERIVATIVES

Phenol derivatives are understandably good choices for potential inhibitors of Tyrosine, since the natural substrate for the enzyme is tyrosine, a phenol derivative.

Because they resemble the natural substrate of the Tyrosinase enzyme, they do not inactivate the enzyme completely and do not destroy the melanocyte cell.  Consequently, they function as SKIN LIGHTENERS, and they must be used continuously to maintain the lightening effect.

Examples

A) Hydroquinone– Hydroquinone is the “gold standard” skin-lightening agent.  It can be found in over-the counter sking lightening products at concentrations under 4%.  Above 4%, a prescription from a physician is required.  Hydroquinone is not the strongest Tyrosine inhibitor.  It is just one of the first used commercially.  It is not without side effects and risks.  Prolonged use of high percentages may be associated with pseudo-ochronosis and cancer.

 

B) Arbutin – Arbutin is naturally-occurring derivative of Hydroquinone.  It can be isolated for the Bearberry plant.  Its structure is identical to Hydroquinone except one of the hydroxyl groups has been modified to contain a sugar residue.  In the human body or skin, the sugar residue is removed enzymatically to form hydroquinone.  Alternative reactions may occur in the body, and it may be converted instead to benzene, a bone-marrow carcinogen.  The native form of arbutin is not as strong as Hydroquinone.  It is found in a variety of skin-lightening products.  Deoxyarbutin is a second generation of Arbutin and appears to be less toxic and a stronger skin lightener.

C)  Resorcinols –  Resorcinols are synthetic and naturally occurring phenol derivatives which inhibit Tyrosinase and are present in certain skin lightening products, including n-Butyl Resorcinol.

2. POLYPHENOLS

Polyphenols are a class of molecules, mostly derived from plant sources, a number of which have been shown to have inhibitory activity against Tyrosinase.  Because they resemble the natural substrate of the Tyrosinase enzyme to a degree because of the aromatic ring structure and the Hydroxyl (-OH) groups, they do not inactivate the enzyme completely and do not destroy the melanocyte cell.  Consequently, they function as SKIN LIGHTENERS and they must be used continuously to maintain the lightening effect.

There are several subtypes:

Flavonoids are a major division of the Polyphenols, which can be further subdivided into subgroups: flavones, flavonols, isoflavones, flavanones, flavanoles and anthocyanidins.

 

A notable member of one of these subgroups (Isoflavones) is Glabridin.  Glabridin, a component of some skin lightening products, is isolated from the root of Glycyrrhiza glabra.  You may know this root as Licorice.  In vitro (the test tube), it exhibits an exceptional ability to inhibit tyrosinase, however there are challenges in getting this compound into the skin.

Another Polyphenol subgroup is the Curcuminoids.  They are compounds naturally derived from Turmeric, some of which demonstrate significant activity in inhibiting Tyrosinase.  A variety of products, masks, and scrubs and Do-It-Yourself skin-lightening approaches utilize Turmeric, and this is the scientific basis behind them.

 

 

STILLBENES

Stillbenes are a chemical class of Polyphenol compounds which include Resveratrol and its derivatives.  Resveratrol is best known for its purported health and longevity benefit, and it being an antioxidant compound found in grapes and red wines.  In vitro, it also shows tyrosinase inhibitory activity, although the precise mechanism of how it inhibits has not been entirely elucidated.  It occasionally appears in skin care products.

 

3.  COMPOUNDS WHICH CHELATE COPPER IONS

Several compounds inhibit Tyrosinase simply by chelating Copper and making it unavailable for the catalytic reaction. Because they somewhat resemble the natural substrate of the Tyrosinase enzyme, they do not inactivate the enzyme completely and do not destroy the melanocyte cell.  Consequently, they function as SKIN LIGHTENERS and they must be used continuously to maintain the lightening effect.

Examples include Kojic Acid, Bis(4-hydroxybenzyl)sulfide, Azealic Acid/Di Carboxylic Acid derivatives and Cysteamine.

A) Kojic acid is a by-product in the fermentation process of malting rice, used in the manufacturing of sake, the Japanese rice wine.  It is produced by a fungus.  It acts as a “chelating agent”, meaning it is able to bind, extract and sequester metal ions.  Presumably, it deactivates Tyrosinase, by chelating Copper ions, and making them unavailable for the catalytic reaction.  Kojic Acid is found in a number of skin-lightening products, including soaps.  It is also used commercially in some food products to prevent them from browning.

Its potential for skin lightening was noted when workers in Sake factories developed light spots on their hands as a part of their jobs.

 

B) Bis(4-hydroxybenzyl)sulfide (T1) is a particularly potent example of a tyrosinase inhibitor.  In fact, it is one of the most powerful inhibitors of Tyrosinase known.  And it has been shown to efficiently reduce melanin in a zebrafish experimental model.

It is felt to work by chelating the Copper ions in the active site, rendering them unable to effectively catalyze the Tyrosinase reaction.  Its effect on the Zebrafish model is astounding.

 

C) Azelaic Acid & Dicarboxylic Acid Derivatives.

Azelaic acid has been used for treatment of skin hyperpigmentation.  It is a carboxylic acid derivative with two carboxylic acid groups (-COOH) groups.  It has been used to treat melasma and post-inflammatory hyperpigmentation successfully and is notably helpful in people with darker complexion.

 

It works by inhibiting Tyrosinase, likely by disturbing or chelating the active site Copper ions rendering the enzyme unable to catalyze the native reaction.    At higher concentrations, it may be cytotoxic to melanocytes.  Studies also suggest that Azelaic acid concentrations have to approach 20% in in vitro solutions to work as well as 4% Hydroquinone.

 

D)  Cysteamine

Cysteamine is structurally related to the amino acid Cysteine.  It differs from Cysteine in the absence of a carboxylate group.  It is also a natural cellular component found in the cell.  Cysteamine inhibits melanin synthesis. Theories how it reduces skin pigment include chelation of Copper ions, which would interfere with Tyrosinase function.  There is also evidence it scavenges dopaquinone as it is formed, removing it from participating in the formation of the melanin polymer.

Cysteamine is known not only to inhibit tyrosinase, but also to lighten skin.  Specifically, a cream version, CYSPERA, has been formulated and has been successful in improving Melasma.  Cyspera is applied to the affected skin area one hour after it has been washed and dried.  Application any sooner may result in irritation.  The cream is left on the skin for a period of 15 minutes to one hour, then washed off.   One of the issues with Cysteamine is its objectionable sulfur smell.   The manufacturers have overcome this strong sulfur smell in the commercial formulation.

A benefit of Cysteamine/Cyspera is that it is very safe and can be used long term.  Hydroquinone is the standard treatment for Melasma, but it cannot be used long term.  Since Melasma is notorious for recurrence, Cysteamine is a better treatment option.  It can be used to treat Post-Inflammatory Hyperpigmentation, but the data about its utility is lacking.

Cysteamine/Cyspera is an over-the-counter product, and no prescription is needed.  Formulations contain other compounds to assist skin lightening including Niacinamide and Ascorbate.  This benefit clearly defines Skin Lightening and Skin Bleaching Difference.

 

4.  OTHER COMPOUNDS -Blood Pressure Medication

Some Blood Pressure medications have the ability to inhibit Tyrosinase or act in the Melanin Biosynthetic pathway to influence it. They DO NOT resemble the natural substrate of the Tyrosinase enzyme, and they do not inactivate the enzyme completely and do not destroy the melanocyte cell.  Consequently, they are predicted to function as SKIN LIGHTENERS and they would need to be used continuously to maintain the lightening effect if proven to demonstrate skin lightening in human subjects.

A) Captopril ([2S]-N-[3-mercapto-2-methylpropionyl]-L-proline) is an Angiotensin converting enzyme (ACE) inhibitor used in the treatment of hypertension and heart failure. The possibility that it may be active against Tyrosinase came from Molecular modeling and mapping of the enzyme and coming up with potential candidate molecules that could be the “key” to fit the Tyrosinase active site “lock”.  The inhibitory effect of captopril is significant against Tyrosinase.  The activity was found to inhibit the tyrosinase activity in dose-dependent manner in B16 (melanocyte) cell line that leads to the inhibition of melanin formation without cytotoxicity.  It is not known whether Captopril prescribed in Heart Failure and Hypertension patients causes their skin lightening as a side-effect.

 

B) Carvedilol is another medication used for the treatment of Hypertension and Heart Failure.  It is a ‘Beta Blocker’, which uses a different class of receptors than Captopril, to relax Blood pressure. In a recent study,  carvedilol was shown to effectively suppress melanogenesis in human melanocytes in cell culture and human skin sample/tissue culture by inhibiting cAMP/protein kinase A/CREB signaling.  This is the system activated by MSH (Melanocyte Stimulating Hormone) binding to MC1R (Melanocortin Receptor) receptor on the melanocyte surface, which induces MITF (microphthalmia-associated transcription factor) to ‘turn on” they synthesis of Tyrosinase and related Genes that produce melanin.

Carvedilol reduced melanin content and cellular tyrosinase activity without compromising cellular viability in normal human melanocytes as well as in mel-Ab immortalized mouse melanocytes. Carvedilol downregulated MITF and Tyrosinase associated synthesis genes – tyrosinase, tyrosinase-related protein (TRP)-1 and TRP-2. Carvedilol downregulates cAMP response element-binding protein (CREB) and lowered the melanin index in ultraviolet-irradiated human skin cultures. The anti-melanogenic effects of carvedilol have potential significance and possible application for skin whitening agents.

No study has indicated whether Carvedilol is known to be associated with the side-effect of skin-lightening in Blood Pressure of Heart Failure.

A specific Anti-Tuberculosis (TB) drug (Ethionamide- second line treatment for multi-Drug-resistant TB), anti-Thyroid medication (methimazole, propylthiouracil), Chemotherapy agents (thiouracil) have been tested and shown to exhibit tyrosinase inhibition.  No products have been developed based on any of these that we can identify.  The importance of compounds like these is that they have well-known safety and toxicity profile, bioavailability information.  So, less resources would be consumed repurposing these medications to new functions.

 

5. MELANOSOME BLOCKERS

Melanosomes carry melanin from melanocytes where they are presented to keratinocytes.   The melanin-containing vesicles are expelled from the melanocytes and then fuse with the membrane of keratinocytes where the melanin serves to protect those cells’ nuclei from radiation damage from the sun.  So long as the blockade of Melanosome does not destroy the cell, the melanocyte can resume transfer.  So, members of this group are expected to function as SKIN LIGHTENERS and must be used continuously to maintain the lightening result.

Hesperidin, a water-soluble citrus flavonoid antioxidant compound identified by screening a herbal compound database/library for potential structural utility, was found to inhibited melanosome transport in melanocyte and showed skin lightening effect in pigmented reconstructed epidermis model.

Hesperidin, although not found to have any Tyrosinase activity, definitely inhibited melanosome transfer from the melanocyte.  It resulted in the accumulation of melanin granules in the melanocyte.  This suggests that hesperidin could be a useful inhibitor of melanosome transport which is safe and could be applied to whitening agent.

 

 

SKIN BLEACHING AGENTS

Back to Skin Lightening and Skin Bleaching? The Difference.  Skin lighteners are typically not toxic to the melanocyte.  They usually slow down the production of the cell by interfering with access by the natural substrate to the active site of the enzyme, by totally or partially inactivating the tyrosinase enzyme, by interference with melanosome transport, or by interference with Transcriptional factors upstream.

So long as the skin-lightening agent is NOT toxic to the melanocyte cell, the cell will simply make more tyrosinase, melanosomes or transcription factors and eventually, melanin production will resume.  Therefore, skin lighteners have to be used daily or a few times daily in order to effect a change that can be visualized. And the amount of the skin-lightening agent applied, the frequency of the application, and the length of time used can be exploited to determine the degree of skin lightening that is achieved.

That is the key essence of the difference of Skin lightening agents and skin bleaching agents.

Skin bleaching agents destroy the melanocyte cells. And if additional melanocyte cells arrive to replace the cells destroyed, they get destroyed too. And because there is no graded effect, the removal of pigment results in white, porcelain-appearing skin comparable to the skin of patients with Albinism (“Albinos”) or patients with Vitiligo.  Instead, the effect is all-or-nothing.

1. Mequinol

Mequinol is di phenol derivative.  Structurally, it resembles Hydroquinone, with one of its two hydroxyl (-OH) modified by an esterification or Methylation to a Methoxy group (-OCH3).  The simple modification has profound implications on its function and usage.  It has an industrial application as an inhibitor of polymer reactions.   Industrial workers exposed to Mequinol developed depigmentation spots and areas on their hands which brought attention to this compound as a potential useful clinical agent.  SOLAGE is the brand name of the prescribed Mequinol and Retinoic acid combination containing Mequinol 2% and 0.01% tretinoin/Retinoic Acid) in an alcohol base.  Although it is discontinued, generic formulations are available through compounding pharmacies.  It can be used as a medication to deliberately depigment dark areas in patients with vitiligo.  The preparation is mainly used for liver spots/solar lentigines and other focal dark spots.

Mequinol alone or in combination with Retinoic Acid (a form of Vitamin A) is a potent irritant of skin.  Redness and painful inflammation may occur to such a significant extent that it can not be tolerated.  Even still, people who use it over extensive parts of skin to bleach it use percentage of Mequinol that are 15% or higher.  The addition of the retinoid helps the penetration of the Mequinol.  It also stimulates rapid cell turnover.  The alcoholic solutions are not for the faint of heart or for those with low pain tolerance.  Users describe the stinging pain after application to the skin “excruciating” for a period of 30 seconds to a minute.

The way Mequinol works in skin bleaching is by binding the Tyrosinase enzyme in the melanocyte.  Rather than the production of the normal product by the enzyme, an unstable set of quinone intermediates and toxic free radicals accumulate, which overcome the levels of the cell’s protective Glutathione antioxidant store, and eventually kill the cell.  Consistent use for prolonged periods would be needed to depopulate the melanocytes to produce uniform skin bleaching.

The mechanisms are not fully understood, but it suggests that IV Glutathione for skin lightening would work against what Mequinol does in the melanocyte, and probably should not be done concurrently.

Mequinol solutions are also used with Q-switched laser therapy to depigment areas on the skin of vitiligo patients with good results.

 

2. Monobenzone

Monobenzone, also called monobenzyl ether of hydroquinone (MBEH) is phenol derivative, which is used topically for medical depigmentation.

 

The mechanism of action by which Monobenzone effects depigmentation of skin is unclear. What is clear by histologic analysis of skin treated with Monobenzone is that the areas are clinically indistinguishable from skin from vitiligo patients.  Since forms of vitiligo are related to immunologic dysregulation, the immune system attacks rather than ignores surface antigens present on the melanocyte.

It has been theorized that Monobenzone reacts with Tyrosinase and generates unstable free radical intermediates which tag melanocyte proteins in the cell.  The surface proteins with the tags (ubiquitin tags) are recognized by the surveillance activity of the immune system. Believing the modified cell-surface antigens is a threat, the immune system reacts to kill the cell, expands its recognition to include other normal melanocyte surface proteins which are not tagged and develops memory cells which are directed at the cells and continuously attacks melanocytes, even ones not exposed to monobenzone and kills them.  The process could be harnessed to help treat Melanoma, a malignant skin cancer that involves transformation of melanocyte cells.

Clinicians have recognized that treating a localized area of skin can result in distant areas of depigmentation that were not exposed to monobenzone.  This suggests that the immune system recognition of melanocytes is destroying melanocytes on other parts of the skin.

Monobenzone is prescribed by dermatologists.  There are commercially available forms which come in 10%, 20%, 40%, 60% and 80%, but sometimes special compounding pharmacies are needed to formulate the product.  People who are seeking to bleach their skin are able to find this compound in powder and cream forms through overseas sellers.  It cannot legally be found outside of a dermatologist’s prescription in the US.

Depigmentation with Monobenzone takes a protracted amount of time to complete.  Changes may be seen in 4 months but can take up to 2 years to complete in some individuals.  And some people do not respond at all to this medication.  Medical depigmentation comes with it a lifelong need for protection from the sun to avoid burns and skin cancers.  The creams commonly contain other compound like kojic acid, Arbutin, Vitamin C (Ascorbate), Vitamin E and Azelaic Acid.

3.   Imiquimod

Imiquimod is an immune system modulation agent.  It is also known by the trade name “Aldara”.  Structure-wise, it is a modified version of the DNA nucleotide base “Adenine”.  As a consequence of its structure, we would expect it to work like many Chemotherapy agents based on modified nucleotide bases by inhibiting DNA synthesis or introducing mutations into DNA to kill bad cells.

 

 

It has been used for the treatment of genital warts and certain skin cancer lesions.  In topical application, it works by stimulating an immune reaction whereby powerful chemical signals are released (Interferon, Interleukins, Tumor Necrosis Factor, etc.) which attract Natural Killer Cells, Macrophages and B-cells.  A known side-effect of the use of this medication was the discovery that in some patients develop a skin depigmentation pattern resembling vitiligo.

Recent studies with Imiquimod have been done to test this compound for the treatment.   The approach to melasma has generally been to lighten the hyperpigmentation area.  However, the rate of recurrence is high, specifically when cessation of the skin lightening agent happens.  Effective treatment may require the skin bleaching approach, to completely eradicate the hyperactive melanocyte population producing recurrent hyperpigmentation.  Approaches using Imiquimod and Lasers have been used to bleach hyperpigmented areas of skin.

 

4. Mercury

Mercury (Hg) compounds, specifically HgCl2 (mercury (II) Chloride) and HgI2(mercury (II) Iodide), are relatively ubiquitous in skin lightening and skin bleaching products obtained from overseas. These are inorganic forms or mercury, but organic compounds of Mercury also exist.

Elemental mercury is the silver liquid found in old thermometers.  Just as you may recall that broken thermometers with mercury spills are treated urgently when they happen in school or science class, the same is true outside of class.  Mercury is extremely toxic to cells and to human beings.  But the zest for white skin has lead people who are reckless, uninformed, ignorant, or desperate to knowingly use products containing Mercury.  These products include Creams, lotions and soaps.  In the US and Canada as well as most countries, Mercury containing products are strictly forbidden, with less 1 ppm allowed in any product.   Some Mercury containing products contain 40,000 times the FDA allowable limit for Mercury.

The reason is because of the grave impact it has on human health.   It is also forbidden, prohibited, illegal and discouraged in all countries, including Asian and African countries but policing the products containing Mercury has been challenging.  Unscrupulous street and commercial vendors simply do not reveal the presence of Mercury in the list of ingredients, understanding that the lay person will not have the resources and means to have the products they product tested in a chemistry lab.  The products then make their way into the US market, typically in ethnic stores catering to ethnic populations.   The State of Minnesota Department of Health has confiscated and analyzed several illicit skin bleaching products containing mercury in their state and found several exceeding safe limits of Mercury.

 

 

 

 

 

 

 

 

 

Mercury works in a few ways to bleach skin.  It is an inhibitor of Tyrosinase in two ways:  It blocks binding by the natural substrate through an effect outside of the active site (noncompetitive inhibition) and when the tyrosinase enzyme is synthesized in the cell, Mercury blocks the incorporation of the Copper ion from assimilating into the active site, such that it never becomes active (suicide inhibition). As long as the product is used, the Tyrosinase will never be functional, and the skin will be bleached.   While the skin bleaching occurs, damage to the brain and central nervous, kidneys and Gastrointestinal system begins.  This will kill some individuals and make others ill and require hospitalization.

 

Mercury compounds should be avoided at all costs.  It is not worth your health and life.

 

5.  Steroids

Several steroids of the corticosteroid family are known to be skin bleaching agents.  A bleaching effect can even be seen after receiving a “cortisone” shot by the family doctor or orthopedic doctor for a soft tissue inflammatory injury or painful tendinitis.

Other corticosteroids have been incorporated in a variety of skin care products to bleach skin.  Some products are sold as stand-alone steroids specifically to bleach skin.  These are generally prohibited in all countries, so vendors work around this inconvenience by simply not including it on the ingredient list.

Steroids due have their place in medicine for the treatment of a variety of immunological, rheumatological conditions (Lupus, Rheumatoid Arthritis) and allergic disorders. Physicians understand the risk/benefit ratios in using these medications, and can surveil, intervene and stop the corticosteroid medication when complications and untoward effects occur.  A lay person using these steroids for skin bleaching cannot, and can suffer complications, including diabetes, skin infections, fungal infections, osteoporosis, Cushingoid syndrome, and Addisonian crisis, just to name a few.  The most common side effects will be Stretch Marks and thinning skin.

Some combinations of products include an antifungal medication, as the manufacturers know the chance of fungal infection is high with frequent use.

Stretch marks are the sign of using illicit skin bleaching products.  If a skin lightening YouTube guru is telling you they use natural skin-lightening products or botanicals to achieve their result, but they cover their shoulder area, underarms or other body parts, or you notice stretch mark lesions on their underarm area or other body areas, chances are the way they lighten their skin was by using steroids or a product containing them, whether they know it or not.  Trust me, they know it.

 

The common forms of corticosteroids found in skin lightening products include: Clobetasol Propionate or Betamethasone Dipropionate.

 

The precise mechanism by which corticosteroid medications bleach skin is unknown.  Here is what we do know.  We know that the effect of steroids is to bind nuclear receptors within cells and control gene expression and cell growth.  It seems plausible that steroid binding to nuclear factors shut down the expression of tyrosinase and related genes in a non-specific manner, preventing their transcription and their translation and induces senescence with the melanocyte to program its premature death.   The suppression of the Melanocyte Stimulation Hormone (MSH) gene specifically assures that the Melanin Biosynthetic Cascade including Melanin Synthesis and Melanosome formation and transport are unable to occur.

Associated changes in the skin cell matrix shift towards an incompetent environment that leads to skin thinning and vascular sparseness.   They also impact immune surveillance leading to susceptibility to infection and further matrix breakdown.

Systemically, the presence of steroids like clobetasol and betamethasone suppress the normal balance and secretion of ACTH from the pituitary gland and cortisol from the adrenal gland.  Chronic usage of the steroid for skin bleaching purposes creates a dependence on the steroid and suppression of the adrenal glands to produce cortisol.  An abrupt withdrawal could put the body in Addisonian crisis, a life-threatening situation that results in low blood pressure, low blood levels of sugar and high blood levels of potassium.

Conclusion

From our discussion, it is clear what the difference between skin lightening and skin bleaching are, and the product options that exist to achieve each result.   Skin lightening compounds tend to be safer over the long term.  The degree of skin lightening can be controlled.   And if complications develop, they can be stopped, usually with no long-term consequence.   The downside is that skin lighteners must be used continually to maintain the result.   This requires discipline, commitment, and expense.

Skin Bleaching agents are different.  They are often all-or-nothing;  meaning they are designed to eliminate the population of melanin-producing cells.   At the completion of depigmentation, the skin is completely white.  Many people do not find porcelain skin a better esthetic than a normal shade of skin.

The consequence of pigment-less skin is a lifetime of protection of the skin to avoid cancers and burns.  During the process, the skin bleaching agents may seriously impact your health in devastating ways.   The potential of causing permanent damage to health and ruining your skin makes skin bleaching with corticosteroids a bad choice.  Like Mercury containing skin bleaching products, they should be avoided.

Hopefully, this discussion has made you wiser and in a position to make better choices on your skin lightening journey.