[Research] Hyperpigmentation treatments split up by mechanism of action

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Hey guys! I thought it'd be helpful to have a nice table to reference that breaks up various hyperpigmentation treatments by their mechanism of action.I'd like to start this off with a big fat disclaimer: I'm not an expert, I have no idea what I'm doing, and I need your help.This is very much a work in progress, and I need help double checking that everything looks right. I want this to primarily be a discussion on how to make this information more accurate. This is going to be a long post, so here's a little table of contents: This section - why a table like this would be useful, where this info comes fromThe tabletmTreatment breakdowns - includes quotes from research overviews so you know why ingredients are categorized the way they areIngredient combos - just an exercise in applying this informationTables, figures, and overviews How is this helpful? There are a lot of ingredients available that can treat hyperpigmentation concerns like post-inflammatory hyperpigmentation and melasma. Treatments can act on different stages of melanin formation (i.e. before, during, or after) using different pathways (such as inhibiting processes that play a role in melanin creation or by breaking down melanin.) A nice figure depicting the process of melanin formation is included down at the bottom.It's recommended to use multiple treatments when addressing hyperpigmentation, since these ingredients should work synergistically with one another by impacting different stages of melanin formation. The more the process is disrupted, the less excess melanin is produced!I found quite a few easy-to-read tables in the overviews I looked at, but often there was information in one that wasn't included in the other, and vice versa. I'm hoping that understanding hyperpigmentation treatments will be made easier by combining the official tables from the people who really know their stuff. Where I got this info: The layout itself is primarily taken from Kim et al., with two sub-heading additions taken from Davis & Callender. I believe that I put these additions in the right place, but would greatly appreciate someone double checking!What category ingredients fall under was all laid out nicely in the overviews - I just combined them. However, I'd still greatly appreciate feedback on everything, especially since the most recent source referenced is from 2014.For the treatment breakdown, I tried to limit the amount of quotes that referenced the same sources.This is primarily intended to be a lay-person friendly table, with recognizable treatments that may be common prescriptions or OTC options. As such, there were certain ingredients & mechanisms of action that I chose not to include in the table. However, I did include them in the treatment breakdown. But just because I'm not super familiar with a treatment doesn't mean it's not relevant/easily accessible, so let me know if you want to see something included in the table! As a reminder, hyperpigmentation can be tricky to treat, and moderate+ cases are best discussed with your derm. This information could be helpful in creating an OTC regimen for mild hyperpigmentation, adding onto treatments you already use, or simply for understanding how these all work together.  Table: Hyperpigmentation treatments split up by mechanism of action Mobile view (now in color!)(because I know there's at least 2 of you) ---BEFORE MELANIN SYNTHESIS---Regulation of tyrosinase transcriptionRetinoidsInhibition of tyrosinase maturationN-acetyl glucosamine---DURING MELANIN SYNTHESIS---Inhibition of tyrosinase activityHydroquinoneMequinol*ArbutinKojic acidAzelaic acidLicoriceResveratrol*Inhibition of melanosome maturationArbutin---AFTER MELANIN SYNTHESIS---Inhibition of melanosome transferHydroquinone*RetinoidsNiacinamideSoyDispersion and removal of melaninRetinoidsAHAsLicorice---ADDITIONAL MECHANISMS---Antioxidant agentsAscorbic acidα-lipoic acidα-tocopherolAnti-inflammatory agentsCorticosteroidsRetinoidsLicorice * - maybe (explained below) Treatment breakdowns Before melanin synthesis Regulation of tyrosinase transcriptionRetinoids“Topical retinoic acid (RA), 0.01% to 1%, reduces pigmentation by inhibition of tyrosinase transcription and significant thickening of the granular layer and epidermis. The number of melanocytes is apparently unaffected, but melanocyte damage is evident.” Roh & Chung, 2009Table 1 from Kim et al., 2012 Did not include quite a few others from Table 1, Kim et al., 2012 Inhibition of tyrosinase maturationN-acetyl glucosamine (NAG)“Its depigmenting ability originates from the inhibition of tyrosinase glycosylation, a step necessary in the production of melanin.” Davis & Callender, 2010 Did not include glucosamine, tunicamycin, glycosphingolipid, calcium d-pantetheine- S-sulphonate from Table 1, Kim et al., 2012 During melanin synthesis Inhibition of tyrosinase activityHydroquinone"Hydroquinone is thought to act by inhibition of tyrosinase, possibly by binding to the enzyme or by interaction with copper molecules at the enzyme’s active site. This leads to altered melanosome formation and increased melanosome destruction, and perhaps even the inhibition of DNA and RNA synthesis." Sheth & Pandya., 2011"Hydroquinone remains the gold standard when treating PIH. It is a phenolic compound that inhibits tyrosinase, thereby reducing the conversion of dihydroxyphenylalanine (DOPA) to melanin." Callender et al., 2011“The mainstay of treatment for PIH remains HQ. It is a phenolic compound that blocks the conversion of dihydroxyphenylalanine (DOPA) to melanin by inhibiting tyrosinase.” Davis & Callender, 2010 Mequinol“Mequinol (4-hydroxyanisole) is a derivative of hydroquinone but may cause less skin irritation than its parent compound. The exact mechanism of action of mequinol is unknown but may involve the competitive inhibition of tyrosinase thereby inhibiting melanin formation.” Callender et al., 2011“The mechanism by which mequinol causes depigmentation may involve a competitive inhibition of tyrosinase; however, the exact pathway is unknown.” Davis & Callender, 2010 Arbutin“Arbutin decreases tyrosinase activity without affecting mRNA expression and inhibits 5,6-dihydroxyindole-2-carboxylic acid (DHICA) polymerase activity.” Kim et al., 2012“Arbutin works by inhibiting tyrosinase activity as well as melanosome maturation, and its efficacy is concentration dependent but higher concentrations can lead to a paradoxical hyperpigmentation.” Callender et al., 2011“Extracted from the dried leaves of the bearberry shrub or pear, cranberry, or blueberry plants, arbutin is another derivative of HQ, but without the melanotoxic effects. Arbutin causes depigmentation by inhibiting not only tyrosinase activity but also melanosome maturation. Although its efficacy is dose-dependent, higher concentrations of arbutin can lead to a paradoxical hyperpigmentation.63 Synthetic forms of arbutin, alpha-arbutin and deoxyarbutin, exhibit greater ability to inhibit tyrosinase than the naturally occurring compound.” Davis & Callender, 2010 Kojic acid“Kojic acid is a molecule produced by Aspergilline oryzae and Penicillium spp. It acts as a tyrosinase inhibitor that works by chelating copper at the enzyme’s active site.” Sheth & Pandya, 2011"Its depigmenting ability originates from a potent inhibition of tyrosinase by chelating copper at the active site of the enzyme.” Davis & Callender, 2010 Azelaic acid“Azelaic acid is a 9-carbon dicarboxylic acid derived from Pityrosporum ovale that acts as a weak reversible competitive inhibitor of tyrosinase.” Sheth & Pandya, 2011"AA has several mechanisms by which it depigments the skin including tyrosinase inhibition as well as selective cytotoxic and antiproliferative effects toward abnormal melanocytes through the inhibition of DNA synthesis and mitochondrial enzymes.” Davis & Callender, 2010 Licorice“Licorice extract inhibits tyrosinase, especially the rate-limiting first step of oxidation.” Sheth & Pandya, 2011“Some of the active ingredients in licorice root extract include glabridin, which inhibits tyrosinase and possesses anti-inflammatory effects, and liquiritin, which does not inhibit tyrosinase but causes depigmentation by melanin dispersion and removal.” Davis & Callender, 2010 ResveratrolTable 1 from Kim et al., 2012Table 1 from Cestari et al., 2014The reason I marked this as 'maybe' in the chart above is because I couldn't find the citations for the statements made in the overviews referenced (and I was too lazy to search any out) Bentisic acid, flavonoids, isoflavonesdid not include in the chart aboveTable 1 from Cestari et al., 2014 4-n-butylresorcinol, 4-hydroxy-anisole, methyl gentisate, 4-5-CAP & derivatives, ellagic acid, oxyresveratrol, aloesin ldid not include in the chart aboveTable 1, Kim et al., 2012 Inhibition of melanosome maturationThis category is from Davis & Callender, 2010.Arbutin“Arbutin works by inhibiting tyrosinase activity as well as melanosome maturation, and its efficacy is concentration dependent but higher concentrations can lead to a paradoxical hyperpigmentation.” Callender et al., 2011“Extracted from the dried leaves of the bearberry shrub or pear, cranberry, or blueberry plants, arbutin is another derivative of HQ, but without the melanotoxic effects. Arbutin causes depigmentation by inhibiting not only tyrosinase activity but also melanosome maturation. Although its efficacy is dose-dependent, higher concentrations of arbutin can lead to a paradoxical hyperpigmentation. Synthetic forms of arbutin, alpha-arbutin and deoxyarbutin, exhibit greater ability to inhibit tyrosinase than the naturally occurring compound.” Davis & Callender, 2010 After melanin synthesis Posttransciptional control of tyrosinaseLinoleic acid, a-linolenic acid, phospholipase D2did not include in the above chartTable 1, Kim et al., 2012 Inhibition of melanosome transferHydroquinoneTable 1 from Cestari et al., 2014The reason I marked this as 'maybe' in the chart above is because I couldn't find the citations for the statements made in the overviews referenced (and I was too lazy to search any out) Retinoids“The mechanism of action is thought to involve stimulation of keratinocyte turnover, decreasing melanosome transfer and allowing greater penetration of other active ingredients.” Sheth & Pandya, 2011 Niacinamide“Hakozaki et al. showed through in vitro studies that niacinamide decreases melanosome transfer by 35–68% without inhibiting tyrosinase activity or cell proliferation.” Callender et al., 2011 Soy“The activation of protease-activated receptor 2 (PAR-2) cell receptors found on keratinocytes mediates the transfer of melanosomes from melanocytes to surrounding keratinocytes. Soy proteins, such as soybean trypsin inhibitor (STI) and Bowman-Birk inhibitor (BBI), inhibit the activation of these cell receptors, and as a result, phagocytosis of melanosomes into keratinocytes is reduced leading to reversible depigmentation.” Davis & Callender, 2010 Serine protease inhibitors, lecthins and neoglycoproteins, RW-50353did not include in the above chartTable 1, Kim et al., 2012 Dispersion and removal of melaninThis category is from Davis & Callender, 2010.Retinoids“Tretinoin works by increasing epidermal turnover thereby facilitating melanin dispersion and removal.” Callender et al., 2011 AHAs“Glycolic acid (GA), found in sugarcane, is a naturally occurring alpha-hydroxy acid (AHA) that induces epidermolysis, disperses basal layer melanin, and increases dermal collagen synthesis.” Davis & Callender, 2010 Licorice“Some of the active ingredients in licorice root extract include glabridin, which inhibits tyrosinase and possesses anti-inflammatory effects, and liquiritin, which does not inhibit tyrosinase but causes depigmentation by melanin dispersion and removal.“ Davis & Callender, 2010 Additional mechanisms Antioxidant agentsAscorbic acid“AA causes skin lightening by interacting with copper ions at the tyrosinase active site and by reducing oxidized dopaquinone, a substrate in the melanin synthetic pathway.” Davis & Callender, 2010“For example, ascorbic acid can interfere with melanization by interaction with copper ions at tyrosinase and reduction of dopaquinone and DHICA oxidation.” Kim et al., 2012 Alpha-lipoic acid“α-lipoic acid, a disulfide derivative of octanoic acid, has been reported to prevent UV-induced oxidative damage, mainly through the down-modulation of NF-κB activation. In addition, this agent is known to inhibit tyrosinase activity by possibly chelating the copper ions." Kim et al., 2012 Alpha-tocopherol"α-Tocopherol and its derivatives can also regulate melanogenesis. The antioxidant property affects the lipid peroxidation of membranes and increases the intracellular glutathione content." Kim et al., 2012 VC-PMG, methimazole, hydrocoumarins, phenol/catecholdid not include in the above chartTable 1, Kim et al., 2012 Anti-inflammatory agentsCorticosteroids"Clinically, it is well-known that topical corticosteroids have strong anti-inflammatory effects. They have been used for the treatment of melasma to decrease irritation caused by hypo-pigmenting agents, and work by the suppression of cytokines through the inhibition of nuclear factor kappa B (NF-κB) activation. Topical steroids can be effective by the suppression of cytokines such as endothelin-1 and GM-CSF, which mediate UV-induced pigmentation." Kim et al., 2012 Retinoids"Retinoids exert multiple biological effects that result in skin lightening including the modulation of cell proliferation, differentiation, and cohesiveness; induction of apoptosis; and expression of anti-inflammatory properties." Davis & Callender, 2010 Licorice"Some of the active ingredients in licorice root extract include glabridin, which inhibits tyrosinase and possesses anti-inflammatory effects, and liquiritin, which does not inhibit tyrosinase but causes depigmentation by melanin dispersion and removal.” Davis & Callender, 2010  Ingredient combosThese are mostly just to show how you could form your own treatment combos using the above table. I tried to cover as many mechanisms of action as possible while limiting it to 3 ingredients.If you end up using the table to pick treatments, please take into consideration your own skin sensitivity and routine. Introduce products one at a time, and listen to your skin!Remember, hyperpigmentation can be tricky to treat and is generally best discussed with your derm. This information could be helpful in creating an OTC regimen for mild hyperpigmentation, adding onto treatments you already use, or simply for understanding how these all work together. The Classic (Kligman's Formula)hydroquinoneDuring (inhibition of tyrosinase acivity), After (inhibition of melanosome transfer)tretinoinBefore (regulation of tyrosinase transcription), After (inhibition of melanosome transfer, dispersion & removal of melanin)corticosteroidsAdditional mechanisms (anti-inflammatory) Gentleniacinamide + NAGAfter (inhibition of melanosome transfer) + Before (inhibition of tyrosinase maturation)licoriceDuring (inhibition of tyrosinase activity), After (dispersion and removal of melanin), Additional mechanisms (anti-inflammatory)soyAfter (inhibition of melanosome transfer) Moderateazelaic acid, or arbutinDuring (inhibition of tyrosinase activity)or During (inhibition of tyrosinase activity, and inhibition of melanosome maturation)niacinamide + NAGAfter (inhibition of melanosome transfer) + Before (inhibition of tyrosinase maturation)ascorbic acidAdditional mechanisms (antioxidant) OTC Kligman'sretinoids (highest strength you can get)Before (regulation of tyrosinase transcription), After (inhibition of melanosome transfer, dispersion & removal of melanin)hydroquinone (if you can get it), azelaic acid (if you can't), or arbutin (if neither are available)During (inhibition of tyrosinase acivity), After (inhibition of melanosome transfer)or During (inhibition of tyrosinase activity)or During (inhibition of tyrosinase activity, and inhibition of melanosome maturation)ascorbic acid or alpha lipoic acidAdditional mechanisms (antioxidant)  Relevant tables & figures:Figure 1 from Ortonne & Bissett, 2008 (cycle of melanin production)Table 1 (imgur) from Kim et al., 2012Table 1 from Cestari et al., 2014Table 2 from Ortonne & Bissett, 2008 Overviews I looked at:Callender, V., St.Surin-Lord, S., Davis, E., & Maclin, M. (2011). Postinflammatory Hyperpigmentation. American Journal Of Clinical Dermatology, 12(2), 87-99. (limited access)Cestari, T., Dantas, L., & Boza, J. (2014). Acquired hyperpigmentations. Anais Brasileiros De Dermatologia, 89(1), 11-25. (full-text)Davis, E.C., & Callender, V.D. (2010). Postinflammatory Hyperpigmentation: A Review of the Epidemiology, Clinical Features, and Treatment Options in Skin of Color. The Journal Of Clinical And Aesthetic Dermatology, 3(7), 20. (full-text)Kim, H., Choi, H., Kim, D., & Park, K. (2012). Topical Hypopigmenting Agents for Pigmentary Disorders and Their Mechanisms of Action. Annals Of Dermatology, 24(1), 1. (full-text)Ortonne, J., & Bissett, D. (2008). Latest Insights into Skin Hyperpigmentation. Journal Of Investigative Dermatology Symposium Proceedings, 13(1), 10-14. (full-text)Roh, M., & Chung, K. (2009). Infraorbital Dark Circles: Definition, Causes, and Treatment Options. Dermatologic Surgery, 35(8), 1163-1171. (full-text)Sheth, V., & Pandya, A. (2011). Melasma: A comprehensive update. Journal Of The American Academy Of Dermatology, 65(4), 699-714. (limited access)  
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