Pharmacological and physical control of skin, hair and eye pigmentation#

First version: 2019-10-13
Last update: 2020-12-27
Persistent link to latest version: https://n2t.net/ark:21206/10022

Abstract

The main substance responsible for skin, hair and eye pigmentation is melanin. We review the biochemical pathways of the endogenous synthesis of melanin and agents known to target these pathways. We address both common agents present in commercially available skin whitening creams and agents that despite not being in widespread use for this purpose have been found to decrease pigmentation, often serendipitously as a salient side effect.

Keywords: skin whitening, skin lightening, skin bleaching, hair lightening, eye depigmentation, eye lightening.

1 Overview

Variation between individuals in skin color, hair color and eye color are mostly due to varying amounts of the dark-colored polymers called generically “melanin”. Pigments acquired through food and embedded within the skin and also blood vessels play a minor role.

There exists a big set of substances known to inhibit the pigmentation of skin with melanin which we call “melanogenesis inhibitors”. There are several mechanism of actions of melanogenesis inhibitors. The molecular pathway of melanogenesis is well-understood; a detailed treatment is outside the scope of this article. For a review of inhibitors of melanogenesis, see Pillaiyar et al. (2017), Chang (2012), Callender et al. (2011), Ebanks et al. (2009), Briganti et al. (2003) and Searle, Riley (1990).

Several products are commercially available for skin whitening; some are taken orally or injected and have a systemic effect; others are topical. Only agents known to be commercially available for systemic effect are mentioned in the following list.

Higa et al. (2000) found that very high doses of the tyrosinase inhibitor kojic acid increases thyroid function in an assay with rats.

2 Discovery and design

Melanogenesis inhibitors have been discovered and developed through several methods, including: screening of synthetic chemical libraries (high throughput screening is occasionally used), screening of plant extracts (Chang et al., 2009a) computational (in silico) search (Choi et al, 2016; Ai et al., 2014), found as a side effect of previously known drugs (Baek, Lee, 2015; Choi, Jee, 2015; Wang et al., 2014; Espín, Wichers, 2001) and exploration of structural analogues of previously known tyrosinase inhibitors (Quing et al., 2015; Yongfu et al., 2013) based on knowledge (in varying degrees) of their structure-activity relationship. Thus, the development and discovery of melanogenesis inhibitors illustrates many of the methods used in drug design. Laijis, Ariff (2019) reviewed the methods used to discover melanogensis inhibitors with a less detailed review of the mechanism of action. Some of the most potent competitive reversible tyrosinase inhibitors are synthetic compounds with a potency hundreds of times that of kojic acid.

3 Mechanism of action

Melanin is the main substance responsible for the color of the skin. Melanin is class of dark polymers generated by the body through the process of melanogenesis. Among the melanin pigmenting the skin and hair, 2 types can be distinguished based on its chemical composition and biological route of synthesis: the black/brown eumelanin and the red/yellow pheomelanin. The variation of skin color among individuals is mostly because of variation of the content of melanin in the skin. Skin with little or no melanin is almost white. Other factors influence skin color in a lesser degree, including the amount of blood in blood vessels (because of the color of blood), skin thickness and content of carotenoids in skin (Whitehead et al., 2012; Pezdric et al., 2015).

Melanin in synthesized in melanosomes which are organelles produced in melanocytes. Melanocytes are cells dedicated to this function that are present in the skin, hair follicles, and other structures of the body. The synthesis of melanin (also called "melanogenesis" and "melanization") involves a chain of enzyme-catalyzed chemical reactions and non-enzyme-catalyzed reactions. The chemical pathways of the synthesis of melanin has been described by many papers; however, it is often oversimplified. The following references are suggested: Kondo, Hearing (2011), Chang (2009) and Slominski et. al. (2004). The main precursor to melanin is L-tyrosine. The first step of melanogenesis is the conversion of L-tyrosine to L-DOPA; this is the first and rate-limiting step and is catalized by the enzyme tyrosinase (TYR) (Slominski et al. 2004, p. 1163). Other enzymes involved in the synthesis include tyrosinase-related protein 1 (TRP1) and tyrosinase-related protein 2 (TRP2); TRP2 is also known as “dopachorome tautomerase” (DCT). L-tyrosine is taken by the melanocytes from the intercellular medium, then transported to the melanosomes. L-tyrosine is also synthesized within the melanocytes from L-phenylalanine by the enzyme phenylalanine hydroxylase (PAH) (Slominski et al. 2004, p. 1164).

Melanosomes are transferred to keratinocytes (the most abundant cell type in the skin). Most of the melanin of skin is found in keratinocytes. Additionally, melanocytes interact with keratinocytes through chemical signaling. See § Preventing the transfer of melanosomes to keratinocytes.

Skin whitening agents work by reducing the presence of melanin in the skin. To accomplish this, there are several possible mechanism of actions (Ebanks et al. 2009) [1]:

  • Inhibition of the activity of tyrosinase: The catalytic action of tyrosinase is inhibited (slowed or nearly stopped) by the skin whitening agent.
  • Inhibition of the expression or activation of tyrosinase: The antimelanogenic agent causes that less tyrosinase is generated or that tyrosinase is not activated to its functional form.
  • Scavenging of the intermediate products of melanin synthesis.
  • Preventing the transfer of melanosomes to keratinocytes.
  • Directly destroying existing melanin.
  • Destroying melanocytes.

3.1 Inhibition of the activity of tyrosinase

Many tyrosinase inhibitors have been discovered or developed. Very many inhibitors of tyrosinase are known; most are of the reversible type [2]. For a review of tyrosinase inhibitors see Chang (2009a). Reviews of patents on tyrosinase inhibitors have been published (Sultan et al. 2016, Pillaiyar et al. 2015).

Upregulation of tyrosinase caused by tyrosinase inhibitors: Several skin whitening agents including some which are tyrosinase inhibitors have been found to cause an increase in the expression of tyrosinase (which by itself would increase melanin synthesis) (Gruber, Holtz 2013, Chang 2013).

3.1.1 Irreversible tyrosinase inhibitors

There are irreversible inhibitors of tyrosinase described in the literature. These have the potential to be very effective for skin whitening and hair lightening, to the point of virtually complete elimination of melanin. Some irreversible inhibitors are listed below.

3.1.2 4-Butylbenzene-1,3-diol

4-Butylbenzene-1,3-diol is a simple compound more often referred to in the pharmacological literature by the names “4-butylresorcinol” and “4-n-butylresorcinol”; these are systematic names. The preferred IUPAC systematic name is 4-butylbenzene-1,3-diol.

Kolbe et al. (2012) compared 4-butylbenzene-1,3-diol with hydroquinone and arbutin in in vitro human reconstructed skin and human subjects; they found that 4-butylresorcinol to be a far more potent inhibitor of melanogenesis than the other examined compounds. Garcia-Jimenez et al. (2016) found that 4-butylbenzene-1,3-diol is a substrate of mushroom tyrosinase. Lee et al. (2016a) found that 4-butylbenzene-1,3-diol increases proteolytic degradation of tyrosinase in vitro in an assay with B16F10 mice cells. Kim et al. (2005) found that 4-butylbenzene-1,3-diol reduces melanogenesis in Mel-Ab mice melanoma cells via direct inhibition of tyrosinase in concentrations at which it is not cytotoxic. Chaudhuri (2015) reviewed the safety and commercial uses of 4-hexylbenzene-1,3-diol, an analogue of 4-butylbenzene-1,3-diol that differes only in the length of the alkyl group. Astra, Oja (2019) determined experimentally the Antoine constants (from which the boiling point follow) for 4-butylbenzene-1,3-diol and related compounds.

3.1.3 Thiazolylresorcinol-based compounds

Thiamidol:Mann et al. (2018a) screened a library of compounds for inhibition of human tyrosinase. They found thiamidol (PubChem CID: 71543007) was the most potent inhibitor among those examined of the competitive and reversible type, with a Ki of 250 nmol/l. Arrowitz et al. (2019) found that a cream with thiamidol was effective and well-tolerated in subjects with melasma. Mann et al. (2018b) examined the structure-activity relationship of Thiazolylresorcinol-based compounds.

3.2 Inhibition of the expression or activation of tyrosinase

Microphthalmia-associated transcription factor (MITF) is the master transcription factor that controls the expression of TYR, TRP1 and TRP2, MART1, PMEL17 and many other important proteins involved in the function of melanocytes [3]. Downregulation of MITF decreases melanogenesis and is a mechanism of action of some skin whitening agents (Chang 2012, Smit et al. 2009). As an heuristic rule, agents acting through downregulation of MITF are more likely to have side effects that selective tyrosinase inhibitors [4] Various signaling pathways and genetic mutations influence the expression of MITF [5].

Inhibitors of melanogenesis whose mechanism of action includes reducing the genetic expression of melanogenic enzymes include caffeoylserotonin (Kim et al. 2012), AP736 (Shin et al. 2015), pomegranate extract (Kang et al. 2015), betulinic acid (Jin et al. 2014) and finasteride (Seo at al. 2018). Yokoyama et al. (2008) found that some histone deacetylase inhibitors lower pigmentation in mice via supression of MITF expression.

3.2.1 The MC1R receptor and cAMP

The melanocortin 1 receptor (MC1R) is a transmembrane and G-protein coupled receptor expressed in melanocytes. MC1R is an important target for the regulation of melanogenesis (Chen at al. 2014; Rodríguez, Setaluri 2014; Yamaguchi, Hearing 2009). Agonism of MC1R increases the ratio of eumelanin to pheomelanin and increases the generation of melanin overall. Loss of function alleles of MC1R are correlated with pale skin, freckles and red hair. We conjecture that pharmacological inhibition of MC1R will increase the proportion of pheomelanin to total melanin thus giving hair a lighter and more reddish color.

MC1R/cAMP signaling pathway[6]: Activation of MC1R causes activation of adenylyl cyclase (AC), which produces cyclic adenosine monophosphate (cAMP), which activates protein kinase A (PKA), which activates (by protein phosphorylation) cAMP response element-binding protein (CREB), which upregulates MITF (CREB is a transcription factor of MITF). Whitening agents that interfere with the MC1R/cAMP signaling pathway have been reviewed by Chang (2012).

cAMP is degraded by phosphodiesterases (PDE). The PDE5 inhibitors sildenafil and vardenafil, the cAMP-promoter IBMX and 8-CPT-cGMP (a cyclic guanosine monophosphate (cGMP) analogue) increase melanin synthesis Zhang et al. (2012).

MC1R ligands. alpha-melanocyte stimulating hormone (α-MSH), beta-melanocyte stimulating hormone (β-MSH) and adrenocorticotropic hormone are endogenous agonists of MC1R (Slominski et al. 2004, p. 1175). According to Yamaguchi, Hearing (2009), agouti signaling protein (ASIP) is the only endogenous antagonist of MC1R. Synthetic MC1R agonists have been designed; examples include the peptides afamelanotide and melanotan II (Chen 2014a). Cain et al. (2006) found several non-peptide small-molecule antagonists of MC1R.

3.3 Preventing the transfer of melanosomes to keratinocytes

Keratinocytes in the skin. Within the skin, melanocytes are present in the basal layer of the epidermis; from these melanocytes originate dendrites that reach keratinocytes [7]. Keratinocytes are the most abundant cell type in the epidermis [8]. In the skin, there are approximately 36 keratinocytes per melanocyte [7]. Keratinocytes are continuously generated in the basal layer of the epidermis and displace older keratinocytes of the skin towards the surface. Le Poole et al. (1993) found that melanocytes are capable of phagocytosis and demonstrated it with latex beads 10 μg in diameter. The literature does not appear to have studied the significance of melanocyte phagocytosis in melanosome transfer.

Melanosome transfer. Melanosomes along with the melanin they contain is transferred from melanocytes to keratinocytes when keratinocytes are low in the epidermis [9]. Keratinocytes carry the melanosomes with them as they move towards the surface. Keratinocytes contribute to skin pigmentation holding the melanin originated in melanocytes and induce melanogenesis through chemical signals directed at melanocytes [5]. The transfer of melanosomes to keratinocytes is a necessary condition for the visible pigmentation of the skin (Wu, Hammer 2014). Blocking this transfer is a mechanism of action of some skin whitening agents (Smit et al. 2009, Ebanks et al. 2009). Skin whitening agents that block melanocyte transfer include niacinamide, heparin (Makino-Okimura et al. 2014), madecassoside (Jung et al. 2013), soybean (Leyden, Wallo. 2011) and Saccharomyces cerevisiae (a species of yeast) (Lee et al. 2015).

3.3.1 Protease-activated receptor 2 (PAR2)

The protease-activated receptor 2 (PAR2) is a transmembrane and G-protein coupled receptor expressed in keratinocytes and involved in melanocyte transfer [10][11]. Antagonists of PAR2 inhibit the transfer of melanosomes and have a skin whitening affects. Agonists of PAR2 have the opposite effect, as expected [11]. The common endogenous agonists of PAR2 are serine proteases which irreversibly activate PAR2 by cleaving a part of the extracellular terminal of this receptor thereby exposing a part of it that subsequently works as a ligand tethered to the reset of the receptor at the molecular scale. Some synthetic agonists of PAR2 are short peptides that imitate the aforesaid tethered ligand but do not cleave the extracellular terminal.

3.3.2 Keratinocyte growth factor receptor (KGFR)

Keratinocyte growth factor receptor (KGFR), UniProt ID: P21802-3, is a receptor tyrosine kinase present in keratinocytes involved in transfer of melanosomes. It is part of the FGFR (fibroblast growth factor receptors) family. It is also known as FGFR2b and FGRF2-IIIb. KGFR was determined to be a splicing variant of FGRF2 by Miki et al. (1992). Cardinali et al. (2005, 2008) found that KGF (keratinocyte growth factor) and ultraviolet radiation promote transfer of melanosomes from melanocytes to keratinocytes. Chen et al. (2009) found that ultraviolet irradiation increases secretion of KGF and KGF without UV irradiation increases amount of tyrosinase and pigmentation. Belleudi et al. (2011) found that increased KGFR expression promote phagocytosis of microscopic latex beads and melanosomes by keratinocytes. Based on the aforementioned studies it would be expected that a KGFR inhibitor causes depigmentation of skin or hair in vivo. Contrary to this, Borad et al. (2014) reported no depigmentation in subjects that received the “pan-FGFR inhibitor” ponatinib; it is possible that a higher dose would achieve a depigmenting effect.

3.4 Chemically-induced vitiligo

Some melanogenesis inhibitors are toxic to melanocytes. These agents can cause permanent depigmentation. They cause well-defined patches of depigmented areas that become bigger with more exposure until they cover the whole area under treatment. The patchy appearance is aesthetically very unfavorable. At least while the patchy phase lasts, the skin in depigmented areas tends to have a notoriously pinkish color instead of a white color. It is recommended that these agents are used with much care or not at all. See Harris (2017) and Gupta et al. (2012). for a review of these agents. See Boissy, Manga (2004) for a review of the mechanism of action. See Ghosh (2010) for a review of the clinical aspects of chemically-induced vitiligo. A non-exhaustive list of agents that induce vitiligo is presented below:

Toosi et al. (2012) examined the mechanism by which 4-TBP and 4-(benzyloxy)phenol cause an autoimmune response. Hariharan et al. (2010) examined the differences of the cytotoxicity towards melanocytes of 4-TBP and 4-(benzyloxy)phenol. They found that 4-TBP causes apoptosis and 4-(benzyloxy)phenol causes non-apoptotic cell death. Both compounds were cytotoxic to fibroblasts in the concentrations that they are toxic to melanocytes.

Hariharan et al. (2011) found that 250 mmol/l (↔ 50 mg/ml) of 4-(benzyloxy)phenol increased the amount of Langerhans cells 2.4 times w.r.t. control and 250 mmol/l (↔ 38 mg/ml) increased it 2.4 times w.r.t. control. In same article, application of 4-(benzyloxy)phenol reduced pigmentation of hair in mice by 20.5 % and reduced pigmentation of skin; application of 4-TBP reduced the same by 2.8 % and increased pigmentation of skin. The experiments in this article compared 4-(benzyloxy)phenol and 4-TBP on the basis of the same amount of substance which gives a 33 % higher dose of 4-(benzyloxy)phenol by mass.

Menter et al. (1993) found that intradermal injections of 4-tert-butylbenzene-1,2-diol (4-TBC) or 4-hydroxyphenol produced depigmentation of skin and hair in mice and that 4-hydroxyphenol but not 4-TBC caused depigmentation away from the site of injection.

3.4.1 Benzene-1,4-diamine

Bajaj et al. (1996) reported a case of depigmentation of the scalp hair and the surrounding skin caused by application of a hair dye with benzene-1,4-diamine (called “paraphenylenediamine” in the paper). Depigmentation persisted 1.5 years after the event with slight repigmentation. The persistence of the depigmentation and the patchy appearance strongly suggest that the mechanism was chemically-induced vitiligo.

3.4.2 4-(Benzyloxy)phenol

4-(Benzyloxy)phenol is used in medical practice in vitiligo cases to extend it to all the skin, thus avoiding the patchy appearance of incomplete vitiligo after the treatment is complete (Grimes, Nashawati 2017). Van den Broon et al. (2011) reviewed the autoimmume response caused by 4-benzyloxyphenol. Several papers [12] attribute the discovery of the chemically-induced vitiligo effect of 4-(benzyloxy)phenol to Oliver et al. (1939).

In an experiment with black guinea pigs Kasraee et al (2006) found that a combination of 4-(benzyloxy)phenol with retinoic acid was more effective in depigmenting skin and reducing the number of melanocytes than 4-(benzyloxy)phenol alone and retinoic acid alone. Samples of a control skin zone had an average of 76 melanocytes; comparable samples treated with 4-(benzyloxy)phenol had an average of 6 melanocytes (7.9 % of control). Pigmentation of hair (fur) was not affected in any treatment. The authors of that study propose the combination of 4-(benzyloxy)phenol alone with retinoic acid for the complete depigmentation of people with vitiligo.

Denton et al. (1962) found that mouse tyrosinase does not directly oxidize 4-(benzyloxy)phenol. In the same article it is presented several experiments with 4-(benzyloxy)phenol in mice. 76 days of oral administration of of 4-(benzyloxy)phenol in an increase dose relative to body mass from 40 mg/kg to 160 mg/kg resulted in visible hair lightening in 3 of 5 mice (60 %). This paper also studied the effects of benzene-1,4-diol and 1-(4-hydroxyphenyl)prop-1-one. They found that subcutaneous injections of 1-(4-hydroxyphenyl)prop-1-one resulted in systemic depigmentation of hair and subcutaneous injections of benzene-1,4-diol resulted in depigmentation of hair in the site of injection.

The stimulator of immume response imiquimod (see below) enhances the depigmenting effect of 4-(benzyloxy)phenol. Webb et al. (2014) examined the combination of 4-(benzyloxy)phenol with imiquimod. Van den Boorn et al. (2010) investigated the combination of 4-(benzyloxy)phenol with imiquimod and cytosine-guanine oligodeoxynucleotides in mice.

3.4.3 4-tert-Butylphenol (4-TBP) and 4-tert-butylbenzene-1,2-diol

In an in-vitro assay Kroll et al. (2005) found that 250 μmol/l (↔ 37.6 μg/ml [13]) of 4-TBP reduces the number of melanocytes in culture of 2 different immortalized cell lines to 59.1 % and 37.5 % of control; the viability of fibroblasts was not affected at 250 μmol/l; it was affected significatively only at 1 000 μmol/l (↔ 150 μg/ml). 4-TBP increased the concentration of HSP70 in cultured melanocytes up to 6.3 times at a TBH dose of 500 μmol/l (↔ 75.1 μg/ml). This study also found that 4-TBP increased the killing of melanocytes mediated by dendritic cells.

Yang et al. (2000) investigated the cytotoxicity of 4-TBP to human melanocytes in culture as a function of their tyrosinase activity. They found that 4-TBP is cytotoxic to human melanocytes including a culture with oculocutaneous albinism type 1, which have a loss of function mutation in the gene that encodes tyrosinase. Thus they conclude that activity of tyrosinase is not neccessary for the cytotoxicity of 4-TBP. This study found that 4-TBP is selectively cytotoxic against melanocytes and fibroblasts compared to keratinocytes. The viability w.r.t. control of melanocytes treated with 500 μmol/l (↔ 75.1 μg/ml) of 4-TBP was ~40 % and treated with 750 μmol/l (↔ 113 μg/ml) was ~15 % (visual estimation from figure 1). This article contains many highly relevant references for the reader interested in the mechanism of action of 4-TBH. Curiously, this study used a compound of uranium in their assays.

Yang, Boissy (1999) found that 4-tert-butylphenol inhibits the activity of tyrosinase in a cell lysate and decreases the expression of tyrosinase in a monoculture of melanocytes.

Manga et al. (2006) found that the cytotoxicity of 4-TBP is mediated by TRP1.

Yang, Boissy (2006) found that 4-TBP is an inhibitor of tyrosinase.

3.4.4 Imiquimod

Imiquimod is a small molecule stimulator of immune response. Topical application can cause depigmentation of skin; the mechanism is apparently through an autoimmune response (chemically-induced vitiligo) and apoptosis of melanocytes. Kim et al. (2010) found that imiquimod causes apoptosis in a culture of normal human melanocytess. Brown et al. (2005) reported a case of local vitiligo-like depigmentation apparently caused by application of imiquimod to male genitals and reviewed previous reports; they found 68 reports of pigmentary changes attributed to imiquimod of which 43 reported depigmentation, 17 reported hyperpigmentation, 7 reported vitiligo and 1 reported hypopigmentation. Jacob, Blyumin (2008) reported a case of topical imiquimod causing a patch of depigmentation in a 65 year old male that persited for at least 18 months.

3.4.5 4-Methoxyphenol

In a non-randomized non-controlled trial in humans with sufferers of vitiligo, Njoo et al. (2000) found that 4-methoxyphenol is effective for the depigmentation of the leftover pigmented areas. The compound was applied as a cream with 25 % (we assume mass fraction) of 4-methoxyphenol. Depigmentation was achieved after 4 months to 12 months of use; this is longer than MBEH. 25 % of the subjects reported mild burning or itching that disappeared when the treatment was stopped.

Riley (1969a) applied a cream of 20 % (we assume mass fraction) 4-methoxyphenol to the skin of guinea pigs; this resulted in depigmentation of skin and later hair. Discontinuation of the treatment resulted in very slow repigmentation from the edges of the depigmented area, suggesting gradual resurgence of melanocytes into the treated area from the untreated area. The same study found that treatment with 2-methoxyphenol did not have a depigmenting effect and 3-methoxyphenol has a very weak depigmenting effect.

Riley (1969b, 1970) found that 4-methoxyphenol is directly cytotoxic to melanocytes.

3.4.6 Olapatidine

Suchi et al. (2008) reported 2 cases of inflammation and depigmentation of the skin around the eye apparenly cauased by olapatidine eye drops in humans that also contain benzalkonium chloride (BAC). The depigmentation persisted months after stopping use of the eye drops; this in indicative of chemically induced vitiligo. Note that no depigmentation of the irises was reported.

3.4.7 Rhododendrol

In an experiment with brown guinea pigs Kuroda et al. (2014) found that rhododendrol reduced the pigmentation in skin and reduced the density of melanocytes in skin from 99 mm−2 to 2.2 mm−2 after 21 days of treatment. After 69 days of non-treatment, this figure increased to 24 mm−2. Ito, Wakamatsu (2018) and Sasaki et al. (2014) examined the mechanism of cytotoxicity of rhododendrol.

3.4.8 Other agents

Bonchak et al. (2014) found that the 5-HT2A agonist 8-DPAT destroys stem cells of melanocytes, which are concentrated around hair follicles.

Denman et al. (2008) found that mice which were treated with a gene gun system to express HSP70 and TRP-2 developed loss of melanocytes and depigmentation of fur including in non-treated areas; this paper attributes the depigmentation to induced immune response against TRP-2 and enhancement of this response by HSP70.

3.5 Inhibition of tyrosine kinases

Tyrosine kinase inhibitors (not to be confused with tyrosinase inhibitors) can cause depigmentation of skin and hair. The mechanism of action is through inhibition of SCFR (Mast/stem cell growth factor receptor Kit; a.k.a. c-Kit, Kit, CD-117. Encoded by gene KIT). See Moss et al. (2003). Dai et al. (2017), Ricci et al. (2016), Galanis, Levis (2015), Robert et al. (2012) reviewed the effects reported in the literature of changes in pigmentation in skin and hair caused by use of tyrosine kinase inhibitors. Martinez-Anton et al. (2018) reviewed the effect of SCFR inhibitors on physiological function including melanogenesis. Botchkareva et al. (2001) examined the importance of SCFR for the pigmentation of hair in mice. Grichnik (2006) reviewed the important role of SCFR in melanogenesis. Some inhibitors of SCFR also inhibit platelet-derived growth factor (PDGF). Karlsson et al. (1999) examined the role of PDGF on normal hair and skin physiology. TKIs that inhibit VEGFR (vasal endothelial growth factor) impair wound healing [14].

Karaman et al. (2008) determined the binding constants of TKIs to tyrosine kinases and computed their main targets and selectivity.

Lee et al. (2014) found that diosmetin (5,7,3’-trihydroxy-4’-methoxyflavone) found in Chrysanthemum morifolium inhibits melanogenesis in vitro through inhibition of SCFR.

Shin, Lee (2013) found that glyceollins, a family of compounds found in soy beans, suppress melanogenesis via inhibition of SCFR.

Nilotinib is a tyrosine kinase inhibitor with activity for SCFR that counter-intuitively increases melanogenesis (Kim et al. 2018, Chang 2018).

3.5.1 Cabozantinib

Zuo et al. (2019) report that cabozantinib caused depigmentation of hair and/or skin in 18 of 41 subjects (44 %) given 60 mg per day; dose was adjusted in some subjects.

3.5.2 Dasatinib

Davis et al. (2011) does not list SCFR among the main targets for dasatinib. Dasatinib can cause hair depigmentation. Compared to other TKI that cause hair depigmentation, dasatinib seems more likely to cause hair whitening (as opposed to a yellow/blond color) and hair loss.

Case reports (not exhaustive):

  • Brazzelli et al. (2012) reported a case of complete depigmentation of scalp hair, eyelashes, eyebrows and partial depigmentation of skin in vitiligo-like patches in a Caucasian male with relatively dark skin treated with 100 mg of dasatinib 2 times per day.
  • Samimi et al. (2013) reported a case of whitening of the scalp hair, eyebrow and eyelashes in a 27 year old woman that received 100 mg per day of dasatinib on regrowth of hair after initial loss (“During her protracted disease course, she experienced an initial anagen effluvium followed by chronic telogen effluvium”).
  • Fujimi et al. (2015) reported a case of depigmentation of scalp hair, eyebrows and eyelashes in a 56 year old woman treated with 90 mg of dasatinib twice daily.
  • Alharbi et al. (2018) reported a case of a 12 year old boy treated with 70 mg per day of dasatinib with localized skin depigmentation.

3.5.3 Imatinib

Cairo-André et al. (2006) found that a concentration of 1 μmol/l of imatinib decreased the number of dendrites and melanogenic activity of melanocytes in vitro and 10 μmol/l caused melanocytes to migrate upwards in in vitro reconstructed epidermis.

3.5.4 Masitinib

Masitinib is a multi-targeted inhibitor of tyrosine kinases with high activity for SCFR. Despite this, we could not find a case report of hair depigmentation caused by masitinib. Pala et al. (2020) reported a case of vitiligo apparently induced by masitinib in a female subject.

3.5.5 Pazopanib

In some papers pazopanib is referred to as GW786034, its research name.

Kobayashi et al. (2014) reported that pazopanib caused hair to grow depigmented in a woman. In the photography they present it can be observed that the natural color of the woman’s hair is black and there are whites and blond stripes corresponding to the time span in which she took pazopanib. Šeparović et al. (2018) reported a similar case of hair depigmentation with pazopanib. Routhouska et al. (2006) reported a case of intense hair depigmentation (from black to white) in a 69 year old woman treated with 1 400 mg of pazopanib. Hurwitz et al. (2006) reported that 6 of 14 subjects (43 %) given a dose ≥ 800 mg per day of pazopanib showed hair depigmentation. Falvre et al. (2006) reported hair depigmentation in 18 of 28 subjects (64 %) among those who received ≥ 50 mg per day and a yellow coloration of skin (prevalence not state) in the same group.

Hurwitz et al. (2009) write that for doses of ≥ 800 mg per day the half-life of pazopanib is 31.1 hours and the most frequent side effects are hypertension, diarrhea, hair depigmentation and nausea.

For a review of the pharmacokinetics of pazopanib, see Verheijen et al. (2017).

3.5.6 Sunitinib

Sunitinib is commonly encountered as the maleate salt. Sunitinib maleate is a yellow powder; the free base is orange (Kassem et al. 2012). In some papers sunitinib is referred to as SU11248, its research name.

Brzezniak, Szabo (2014) reported a case of hair depigmentation in a woman caused by 50 mg of sunitinib per day. Hartmann, Kanz (2008) reported a case of depigmentation of hair caused by 50 mg of sunitinib per day. Bansal et al. (2014) reported a case of partial depigmentation of body hair and a simultaneous adverse cutaneous reaction in an Indian man treated with 50 mg per day of sunitinib. Davis et al. (2011) examined the pharmacodynamics of several tyrosine kinase inhibitors; they found that sunitinib and masitinib are the only compound among the compound examined whose main target is SCFR and rated sunitinib as the most selective inhibitor for SCFR. Rosenbaum et al. (2008) reviewed clinical trails of sunitinib; among studies that used a dose of 50 mg per day, they found a prevalence of hair depigmentation in any degree of 16 %; they found that yellow pigmentation of the skin is a common effect of sunitinib; this pigmentation goes away in the span of weeks after discontinuation of sunitinib.

3.6 Directly destroying existing melanin

Several species of fungi produce enzymes that reduce pigmentation by degrading melanin. These enzymes often require the presence of hydrogen peroxide and sometimes the presence of Mg+2 ions to work. Nagasaki et al. (2008) proposed melanin-degrading enzymes as a safer alternative to hydrogen peroxide for cosmetic direct hair depigmentation.

The enzyme lignin peroxidase produced by the fungus Phanerochaete chrysosporium has been studied as an ingredient suitable for skin-whitening: In a double-blind placebo-controlled split-face randomized study Tess et al. (2011) found this enzyme to be effective and superior to hydroquinone in skin whitening. In a non-controlled study Zhong et al. (2015) applied this enzyme to volunteers with facial melasma during 8 weeks; the treatment was found effective in reducing pigmentation in both skin affected by melasma and skin unaffected by melasma.

3.7 Serotonin signaling

Melanocytes express serotonin receptors and are capable of producing serotonin. Pharmacological interference with the serotonin system of melanocytes can result in either increased or decreased melanin synthesis. Serotonin itself is a weak inhibitor of tyrosinase (Yamazaki et al. 2009) with 0.11 times the potency of kojic acid [15]. Nonetheless, serotonin increases synthesis of melanin when its overall effect on melanocytes (as opposed to isolated tyrosinase) is evaluated (Zhou et al. 2016). Activation of 5-HT2B receptors with BW-723C86 inhibits melanogenesis (Oh et al. 2016) while activation of 5-HT2A receptors with DOI promotes melanogenesis (Lee 2011). The serotonin reuptake inhibitor 6-nitroquipazine inhibits melanogenesis in-vitro (McEwan, Parsons 1987).

4 Other agents causing hair lightening

Shimshek et al. (2016) found that the compound NB-360 caused fur depigmentation in mice and reduced melanogenesis in a culture of human melanocytes.

Chloroquine and hydroxychloroquine further lighten hair in people who already have light hair. Bubblin, Thompson (1992) reviewed case reports of hair lightening caused by chroloquine and hydroxychloroquine. According to Bubblin, Thompson (1992), the first paper to report the hair lightening efect of chloroquine was that of Alving et al. (1948).

Plonka et al. (2006) found that oral administration of a high dose of zinc sulfate caused depigmentation of fur in mice to a light brown-yellow color. This paper also includes a review of the opposing roles of zinc in melanogenesis.

Mephenesin can make hair grow blond in people with dark hair during the duration of its use. Spillane (1963) reported 6 such cases with total daily doses around 5 g-10 g. Turner (1963) reported 3 further cases of hair depigmentation with mephenesin with daily doses between 4.5 and 8 g. Both case reports mention that skin did not change color.

Schoental (1971) found that the DNA disruptor methyl N-methyl-N-nitrosocarbamate (a.k.a. N-methyl-N-nitrosourethane) causes fur depigmentation in mice and rabbits; this paper says: “Similar permanent depigmentation of hair was observed in pigmented mice also after s.c. injections of N-ethyl-N-nitrosourethane and of elaiomycin.”.

Jimbow et al. (1974) found that subcutaneous injections of hydroquinone cause hair depigmentation in mice.

Schoental et al. (1978) found that intraperitoneal injections of calcium pantothenate (vitamin B5) caused hair depigmentation in mice. http://www.keratin.com/as/as008.shtml lists some studies about drugs known to cause color changes in hair.

Hair removal with incoherent intensed pulsed light (IIPL) or laser often causes white depigmentation of the remaining hair in the affected area. Radmanesh (2004) reported a case where IIPL caused blond depigmentation of facial hair in a woman.

4.1 Green hair

Exposure of light hair to water with a high concentration of copper ions occasionally results in the hair acquiring a greenish color (Roomans, Forslind 1980).

Pulos et al. (2019) and Callander et al. (1989) reported cases of green hair apparently caused by systemic use of propofol in people with light hair (natural in one case, dyed in another). The conjectured mechanism is the deposition of a green metabolite of propofol in the hair.

5 Eye lightening

The eyes are harder to depigment than the skin and hair because the melanin in the eyes is persistent. The melanin in hair and skin is removed with normal hair growth and skin renewal.

Doyle, Liu (1999) reported a case of depigmentation of the irises apparently caused by levobunolol eye drops.

Pulsed laser can disrupt the melanin of the iris and elicit a response where the body body removes the melanin through the span of weeks, leaving the eye in its structural color; this can be blue, purple or gray; the most common structural color is blue. This technique appears to be already in use, elective and for correction of heterochromia (irises of eyes of different color). However there is scarse research in the literature. Yildirim et al. (2016) tested this technique on rabbits; they used a frequency-doubled neodymium-doped yttrium aluminum garnet laser (Nd:YAG) to depigment the irises with good restults. Basoglu, Çelik (2017) used a Nd:YAG laser on a human subject with heterochromia with blue and brown to even the color to blue.

6 Notes

  1. Chang (2009a) writes:

    In addition to inhibition of tyrosinase catalytic activity, other approaches to treat hyperpigmentation include inhibition of tyrosinase mRNA transcription, aberration of tyrosinase glycosylation and maturation, acceleration of tyrosinase degradation, interference with melanosome maturation and transfer, inhibition of inflammation-induced melanogenic response, and acceleration of skin turnover. Accordingly, a huge number of depigmenting agents or whitening agents developed by those alternative approaches have been successfully identified and deeply reviewed in many articles [references omitted]

  2. :
  3. Chang (2009a) writes:

    In contrast to the huge number of reversible inhibitors has been identified, rarely irreversible inhibitors of tyrosinase were found until now. These irreversible inhibitors, which are also called specific inactivators, can form irreversibly covalent bond with the target enzyme and then inactivate it.

  4. . For a review of tyrosinase inhibitors see
  5. Ebanks et al. (2009) write:

    The transcriptional level is the first stage by which the expression of tyrosinase and related melanogenic enzymes may be modulated. Influential in this process, the microphthalmia-associated transcription factor (MITF) is a basic helix-loop-helix leucine zipper transcription factor that regulates melanocyte cellular differentiation as well as the transcription of melanogenic enzymes (tyrosinase, TYRP1 and TYRP2) and melanosome structural proteins (MART-1 and PMEL17) [references omitted].

    Chang (2012) writes:

    In addition to being involved in the survival, proliferation, and differentiation of melanocytes, MITF is the master regulator of melanogenesis in melanocytes via binding to the M box of a promoter region and regulating the gene expression of tyrosinase, TRP-1, and TRP-2 [references omitted]. The up-regulation of MITF activity activates the expression of the melanogenesis-related enzymes, thus stimulating melanogenesis. In contrast, the down-regulation of MITF activity depresses the expression of the related enzymes, thereby inhibiting melanogenesis.

  6. . Downregulation of MITF decreases melanogenesis and is a mechanism of action of some skin whitening agents (
  7. Chang 2012 writes:.

    Because tyrosinase is produced only by melanocytic cells, tyrosinase inhibitors have highly specific targeting to melanogenesis in the cells without other side effects. In contrast, those melanogenesis inhibitors targeting to the tyrosinase gene expressions or protein degradations are rarely used as clinical hypopigmenting agents, due to their non-specific and global effects via intracellular signaling pathways.

  8. Various signaling pathways and genetic mutations influence the expression of MITF
  9. Many papers have described the signaling pathways affecting melanogenesis and other functions of melanocytes. The following reviews are suggested reading (all of which are available online at no cost): For a description with emphasis on the relation with skin whitening, see Chang (2012) or Smit et al. (2009). For a description with emphasis on physiology, see Yamaguchi, Hearing (2009) or Kondo (2011). For a description of intra-melanocyte signaling pathways, saee Imokawa, Ishida (2014). An extensive and detailed review was written by Slominski et. al. (2004). See also Ho-Sung et al. (2015), Hideki et al. (2015).

  10. .
  11. Chang (2012) writes:

    Alpha melanocyte-stimulating hormone (α-MSH), a peptide derived from proopiomelanocortin (POMC), regulates melanogenesis via a cyclic adenosine monophosphate (cAMP)-dependent pathway [references omitted]. When binding to its receptor, melanocortin receptor 1 (MC1R), on the membrane of melanocytes, the hormone activates adenylate cyclase (AC) to produce cAMP as an intracellular second message via a G-protein-coupled receptor (GPCR)-type activation. cAMP activates protein kinase A (PKA), which then activates the gene expression of MITF via phosphorylation of the cAMP response element-binding protein (CREB). Finally, MITF efficiently activates the melanogenesis-related enzymes and stimulates melanogenesis. Once α-MSH binds to MC1R, up to a 100-fold increase in melanogenesis attends. In addition to α-MSH, other POMC-derived peptides, such as β-MSH and adrenocorticotropic hormone (ACTH), also stimulate melanogenesis via the same pathway.

    D’Orazio et al. (2013) writes:

    α-MSH binding to melanocortin 1 receptor (MC1R) on melanocytes in the basal epidermis generates the second messenger cAMP via interactions between MC1R and adenylyl cyclase, and leads to activation of protein kinase A and the cAMP responsive binding element (CREB) and microphthalmia (Mitf) transcription factors. CREB and Mitf directly enhance melanin production by raising levels of tyrosinase and other melanin biosynthetic enzymes. Thus, MSH-MC1R signaling leads to enhanced pigment synthesis by melanocytes and accumulation of melanin by epidermal keratinocytes.

    [etcetera]

    The MC1R is found on the surface of melanocytes where it binds to α-melanocyte stimulating hormone (MSH) and transmits differentiation signals into the cell through activation of adenylyl cyclase and generation of cAMP [references omitted]. cAMP signaling leads to activation of the protein kinase A (PKA) cascade which, in turn, leads to increased levels and/or activity of many melanogenic enzymes to enhance production and export of melanin by melanocytes [>references and figure omitted].

    See also Chen 2014a, Rodríguez 2014 and Lee 2013.

  12. : Activation of MC1R causes activation of adenylyl cyclase (AC), which produces cyclic adenosine monophosphate (cAMP), which activates protein kinase A (PKA), which activates (by protein phosphorylation) cAMP response element-binding protein (CREB), which upregulates MITF (CREB is a transcription factor of MITF). Whitening agents that interfere with the MC1R/cAMP signaling pathway have been reviewed by
  13. Smit et al. (2009) write:

    In the skin, melanocytes are situated on the basal layer which separates dermis and epidermis. One melanocyte is surrounded by approximately 36 keratinocytes. Together, they form the so-called epidermal melanin unit. The melanin produced and stored inside the melanocyte in the melanosomal compartment is transported via dendrites to the overlaying keratinocytes.

    Ebanks et al. (2009) write:

    Each melanocyte resides in the basal epithelial layer and, by virtue of its dendrites, interacts with approximately 36 keratinocytes to transfer melanosomes and protect the skin from photo-induced carcinogenesis. Furthermore, the amount and type of melanin produced and transferred to the keratinocytes with subsequent incorporation, aggregation and degradation influences skin complexion coloration [reference omitted].

    Wu, Hammer (2014) describe the number of keratinocytes per melanocyte as above 40.

  14. . Keratinocytes are the most abundant cell type in the epidermis
  15. D’Orazio et al. (2013) write:

    Keratinocytes are the most abundant cells in the epidermis and are characterized by their expression of cytokeratins and formation of desmosomes and tight junctions with each other to form an effective physicochemical barrier.

  16. . In the skin, there are approximately 36 keratinocytes per melanocyte
  17. Research about the mechanism of melanosome transfer has been reviewed by Wu, Hammer (2014).

  18. . Keratinocytes carry the melanosomes with them as they move towards the surface. Keratinocytes contribute to skin pigmentation holding the melanin originated in melanocytes and induce melanogenesis through chemical signals directed at melanocytes
  19. Jung et al. (2013) write:

    Protease-activated receptor (PAR)-2 is a member of a novel G-protein-coupled seven-transmembrane receptor family. In epidermis, PAR-2 is expressed in keratinocytes [references omitted], but not melanocytes [references omitted]. A central role for PAR-2 in keratinocyte uptake of melanosomes has been established [references omitted]. PAR-2 has been linked to the upregulation of COX-2 and the release of arachidonic acid and secretion of PGE2 and PGF2α [references omitted]. Several reports have suggested that PAR-2 mediates cutaneous pigmentation through increased uptake of melanosomes by keratinocytes and by the release of PGE2 and PGF2α that stimulate melanocyte dendricity [references omitted].

  20. References about PAR2 and its role in skin pigmentation: Kim et al. (2016), Choi et al. (2014), Makino-Okamura (2014), Wu, Hammer (2014), Ando et al. (2012), Ando et al. (2010).

  21. . Antagonists of PAR2 inhibit the transfer of melanosomes and have a skin whitening affects. Agonists of PAR2 have the opposite effect, as expected
  22. For example, van den Boorn et al. (2010) write (other references omitted):

    Monobenzone is the most potent skin depigmenting agent, discovered by Oliver et al. in 1939.

  23. attribute the discovery of the chemically-induced vitiligo effect of 4-(benzyloxy)phenol to
  24. Mass concentration computed using a molar mass of 150.22 g/mol for 4-TBP, then reported rounded to 3 digits.
  25. ) of 4-TBP reduces the number of melanocytes in culture of 2 different immortalized cell lines to 59.1 % and 37.5 % of control; the viability of fibroblasts was not affected at 250 μmol/l; it was affected significatively only at
  26. Macdonald et al. (2015) write (references elided):

    Inhibition of the VEGF pathway can disrupt wound repair and result in delayed wound healing in a dose-dependent fashion and fistula formation. This becomes a consideration for surgical nplanning in both the adjuvant and neoadjuvantsettings.

  27. .
  28. Computed from the data reported by Yamazaki et. al. (2009): IC50(serotonin)=550 µmol/l. IC50(kojic acid)=68 µmol/l.
  29. . Nonetheless, serotonin increases synthesis of melanin when its overall effect on melanocytes (as opposed to isolated tyrosinase) is evaluated (

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