Melanogenesis and hydroquionone 
Review paper 
MELANOGENESIS AND HYDROQUINONE 
G. Noto, G. Pravata and M. Arico 
SUMMARY 
Mammalian melanocytes synthesize melanin in specific intracellular organelles, the melanosomes, whkh are 
afterward carried along melanocytic dendrites, injected into keratinocytes and, finally, degraded and eliminated 
by the epidermal turnover. Melanogenesis, i.e., the synthesis of melanosomes and melanin, is a cascade of 
events controlled by factors which are either interna! and external to the melanocyte. Melanins are divided 
into eumelanins, pheomelanins, mixed melanins, tricochromes, neuromelanins, and, recently oxymelanins. The 
role of sulphydrilic compounds (cystein and glutation) for determining the kind of melanin, in particular for 
pheomelanins, does not seem to be due to their absolute presence or absence, but rather to their 
concentration in a certain moment. Eumelanogenesis and pheomelanogenesis are conditioned by a balance 
between tyrosinase and natura! melanogenic inhibitors, as lactic acid, ascorbic acid and glutathione. 
Among agents that are capable to interfere with melanocytic metabolism there are various cytotoxic 
compounds, some of which are selective for the melanocyte, as hydroquinone (HQ) and his derivatives. HQ 
is a compound capable of inhibiting melanogenesis acting as a substrate for tyrosinase. This competitive action 
does not seem to inactivate tyrosinase, thus the activity is reversible. The tendency of HQ to undergo 
hydroxylation and dehydrogenation, with formation of highly reacting quinones, i.e ., hydroxybenzoquinone, p-
benzoquinone and their derivatives, may suggest a biochemical base to understand the melanocytic cytotoxic 
effects, interfering with melanization and causing focal degradation of melanosomes. The complex activity of 
HQ on pigmentation, although not yet completely known, rnight also explain the main side-effects of topically-
applied HQ, i.e ., toxic depigmentation and exogenous ochronosis, as the active concentration is next to the 
toxic one. 
KEY WORDS: 
melanogenesis, hydroquinone, selective effects 
MELANOGENESIS 
Skin pigmentation due to melanin is regulated by 
two components: 1) the pigmentation constitutive!y 
acta dermatovenerologica A.P A. Vol 4, 95, No Z 
expressed, according with the genetic program, 
independed of exposure to ultraviolet (UV) rays 
( constitutional skin tanning); 2) the pigmentation 
due to direct exposure to UV (immediate and 
9 
Melanogenesis and hydroquionone 
delayed tanning). Mammalian melanocytes synthesize 
melanin in specific intracellular organelles, the 
melanosomes, which are afterward carried along 
melanocytic dendrites, injected into keratinocytes 
and, finally, degraded and eliminated by the epidermal 
turno ver. 
Pigmentation control is complex, as shown by the 
wide range of colours in all species of animals . 
Genetic control of pigmentation involves, in mice, 
more than 60 loci, divided into two main groups: 1) 
loci controlling melanoblasts' survival and differentiation 
during embryogenesis, and 2) loci controlling the 
phenotypic differentiation of melanocytes, e.g., the 
c-locus for tyrosinase, the a-locus for quantity and 
distribution of pheomelanins and eumelanins and 
the b-locus for eumelanins. Functionally, these loci 
can be divided into four major classes: class A 
defines migration, proliferation and survival of 
melanocytes; class B controls quantity of melanin 
produced; class C determines the type of melanin 
synthesized; class D establishes shape and ultra-
stmctural features of melanocytes (1). 
Moreover, melanocytes are an excellent model for 
evaluating hormonal modulatory activity on proli-
feration and differentiation; in fact, many studies 
have shown that these cells are a target not only 
for the melanocytic stimulating hormone (MSH), 
but even for insuli.n, glucocorticoids and prostagla.ndins. 
Also i.nflammatory and immu.nogenic cytokines internet 
with melanocytes controlling pigmentatio.n, growth, 
differe.ntiation, immunologic susceptibility and 
cytotoxicity, production of cytokines and matrix proteins 
and cell movement (2). For instance, interleukin-1 
(IL-1) alpha and beta, IL-6, TNF-alpha and gra-
nulocyte/mo.nocyte colony stimulating factor (GM-
CSF) are capable of inhibiting the melanocytic 
response, without modifying the basal tyrosinase 
activity to MSH-alpha, prostaglandins El and E2, 
and to isobuthyl-methyl-xanthine. Melanocytes synthe-
size arachidonic acid metabolites and various cytokines, 
suggesting their active role in the skin immune 
system (3). Moreover, it is well known that for a 
normal growth of cultured melanocytic cells various 
growth factors are required, as insulin, alpha-MSH, 
basic fibroblast growth factor and the phorbol esther 
TPA (4). 
Melanogenesis, i.e. synthesis of melanosomes and 
melanin, is a cascade of events controlled by factors 
which are either interna! or external to the melanocyte 
(Tab. I). The membranous stmcture of melanosomes 
regulates the recognition and selection of these 
informations and thus the differentiation of 
melanosomes as well as the kind of melanin. In the 
10 
melanosome two main components can be di-
stinguished: the lipidic one, initially located at the 
external surface, and the proteic one, constituting 
the central part of the melanosome. The former is 
very important for functional regulation, whereas 
the latter, including tyrosinase and his regulatory 
factors, for stmctural differentiation. Mela.nogenesis 
is conditioned by UV, hormones and by the substrate 
available. 
Melanins are distinguished into eumelanins, pheo-
melanins, mixed melanins, tricochromes, neuromelanins, 
and, recently oxymelanins (5). The role of sulphydrilic 
compounds ( cystein and glutation) for determining 
the kind of melanin, in particular for pheomelanins, 
does not seem to be due to their absolute presence 
or absence, but rather to their concentration at a 
certain moment. Eumelanogenesis and pheomelano-
genesis are conditioned by a balance between tyrosinase 
and natural melanogenic inhibitors, as lactic acid, 
ascorbic acid and glutathione (6). Morphogenesis of 
melanosomes could not follow, from the beginning, 
the eumelanic or the pheomelanic pathway, but 
both types may coexist, in so-called "mosaic melano-
somes", before definitive differentiation. Variation 
of melanogenesis type could be controlled by stmctural 
and functional availability of the vesico-globular bodies 
associated with HMSA5 glicoproteins, as the number 
of these bodies is different in eumelanoge.nesis and 
pheomelanogenesis; they could play an important 
role not only in the stmctural organization of the 
melanosome matrix, but also as carriers of pre- or 
post-tyrosinase regulatory factors (7). 
HYDROQUINONE 
Among agents that are capable to interfere with 
melanocytic metabolism there are various cytotoxic 
compounds, some of which are selective for the 
melanocyte, as hydroquinone (HQ) and his derivatives. 
HQ is one of the most common compounds used 
for treatment of melasma, chloasma a.nd other 
disorders characterized by increased cutaneous 
pigmentation, i.e ., cutaneous melanoses. 
The activity of HQ was known since 1936, when 
Oettel (8) showed that black hairs of cats treated 
with HQ per os gradually cleared, becoming gray. 
Martin and Ansbacher (9) confirmed the HQ activity 
in young mice, determining loss of hair pigment 
reversible in a period comprised between 4 and 20 
weeks. Further contributions, during the subsequent 
years, demonstrated that even topical application, as 
well as local injection of HQ, is effective to clear 
skin and hair pigmentation of mouse, guinea pig 
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Melanogenesis and hydroquionone 
Table I: The steps of melanogenesis 
Structural protein of the melanosome + tirosinase and regulatory factors 
Dopaquinone 
J, 
5,6-dihydroxyndole 
J, 
Eumelanin 
and man. 
Histologic and electron-microscopy investigations 
focused the specific action of HQ on skin and hair 
melanocytes. Previous studies had suggested that the 
main action of HQ is inhibition of melanocytic 
tyrosinase, with subsequent decreasing of melanin 
production and depigmentation (10). Further investi-
gations revealed that HQ acts also as cytotoxic 
agent (11-12). Jimbow confirmed, with ultrastructural 
investigations, that HQ activity is selective for follicular 
and skin melanocytes; moreover HQ can induce 
inflammation with activation of Langerhans' cells 
(13). 
Lerner and coworkers (14) demonstrated that HQ 
is less effective than tyrosine and DOPA as a 
substrate for mammalian tyrosinase, but it could 
participate as a substrate in the partial melanization 
in presence of tyrosine. In fact, HQ oxidation may 
give rise to free radicals (semi-quinones-like) capable 
to disrupt the membrane by enzymatic oxidation. It 
could be conceivable that HQ, topically applied or 
locally injected, may generate free radicals within 
the tyrosine-tyrosinase system in melanosome and 
melanocytes. These radicals could interfere with 
tyrosine oxidation and melanosome melanization 
causing focal degradation of the matrix and changes 
of melanosome membrane. Riley (15) demonstrated 
that phenolic derivatives may generate, by means of 
Table II. Possible mechanisms of hidroquinone activity 
a) competitive substrate for tyrosinase; 
b) chemical link with the intermediate compounds 
of melanin synthesis, blocking melanin formation; 
c) focal degradation of melanosomes, by means 
of formation of free radicals in melanin and/or 
intermediate compounds. 
acta dermatovenerologica A.P.A. Vol 4, 95, No 1 
Dopaquinone and cysteine 
J, 
Cysteinil-dopa 
J, 
Pheomelanin 
enzymatic oxidation by tyrosinase, free radicals which 
can cause lipidic oxidation and cellular damage. 
Jimbow (13) showed that HQ attacks nuclear and 
cytoplasmic membranes of melanocytes, with disruption 
and degradation of membranous organelles up to 
necrosis. Hu (12), analyzing in vitro melanosome 
movements in melanocytic dendrites in order to 
evaluate the effectiveness of HQ, found reduced 
movements at concentrations of 1.25 - 2.5 mcg/ml. 
These concentrations inhibited also DNA and RNA 
synthesis. Penney et al. (16) revealed a selective 
inhibition of HQ on melanocyte metabolism compared 
to other cell-types, demonstrating a primary effect 
on RNA synthesis, suggesting that the depigmenting 
activity of HQ is prevalently due to a direct action 
on melanocyte metabolism more than a specific 
effect on melanin synthesis. Morphological effects of 
HQ are documented by reduction of melanized 
melanosomes and by the presence of abnormally 
pigmented melanosomes, these latters show an altered 
core and are rapidly degraded by keratinocytes. The 
direct cellular damages of melanocytes are disruption 
and lysis of membranous organelles, up to cellular 
necrosis. 
The abnormal melanization induced by HQ could 
be due to the following actions: 
a) HQ, similar to tyrosine, could act as a competitive 
substrate for tyrosinase; 
b) HQ could be chemically linked with the inter-
mediate compounds of melanin synthesis, blocking 
melanin formation; 
c) HQ could cause focal degradation of melanosomes, 
by means of formation of free radicals in melanin 
and/or intermediate compounds. 
The enzyme tyrosinase seems to mediate almo.st 
ali the effects of HQ on skin depigmentation, but 
the biochemical events that give rise to melanotoxic 
effects are not completely understood. 
11 
Melanogenesis and hydroquionone 
CONCLUSIONS 
Finally, also on the basis of the most recent "in 
vitro" contributions (17-19), we can draw the following 
considerations: a) HQ is a compound capable of 
inhibiting melanogenesis acting as a substrate for 
tyrosinase (17-18); b) this competitive action does 
not seem to inactivate tyrosinase, thus the activity is 
reversible; c) the tendency of HQ to undergo 
hydroxylation and dehydrogenation, with formation 
of highly reacting quinones, i.e., hydroxybenzoquinone, 
p-benzoquinone and their derivatives, may suggest a 
biochemical base to understand the melanocytic 
cytotoxic effects, interfering with melanization and 
causing focal degradation of melanosomes. 
Moreover, the complex activity of HQ on pig-
mentation (Tab. II), although not yet completely 
known, might also explain the main side-effects of 
topically-applied HQ, i.e., toxic depigmentation and 
exogenous ochronosis, as the active concentration of 
HQ is next to the toxic one. 
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AUTHORS' ADDRESSES 
12 
Mario Arico MD, PhD, professor of dermatology, Department of Dermatology and Venereology 
University of Palermo, Policlinico "P. Giaccone" Via del Vespro 129, 1-90127 Palermo, Italy. 
Giuseppe Noto MD, same address 
Gabriella Pravata MD, same address 
acta dermatovenerologica A.P.A. Vol 4, 95, No 1