Regulation of human skin pigmentation and responses to ultraviolet radiation

Regulation of human skin pigmentation and responsesto ultraviolet radiation

Yoshinori Miyamura1�, Sergio G. Coelho1�,

Rainer Wolber2, Sharon A. Miller3, Kazumasa

Wakamatsu4, Barbara Z. Zmudzka3, Shosuke

Ito4, Christoph Smuda2, Thierry Passeron1,

Wonseon Choi1, Jan Batzer2, Yuji Yamaguchi1,

Janusz Z. Beer3 and Vincent J. Hearing1*

1Laboratory of Cell Biology, National Cancer Institute, National

Institutes of Health, Bethesda, MD, USA2Department of Skin Research, Beiersdorf AG, Hamburg, Germany3Center for Devices and Radiological Health, Food and Drug

Administration, Rockville, MD, USA4Department of Chemistry, Fujita Health University School of

Health Sciences, Toyoake, Japan

*Address correspondence to Vincent J. Hearing,

e-mail: [email protected]

Summary

Pigmentation of human skin is closely involved in

protection against environmental stresses, in partic-

ular exposure to ultraviolet (UV) radiation. It is well

known that darker skin is significantly more resist-

ant to the damaging effects of UV, such as photo-

carcinogenesis and photoaging, than is lighter skin.

Constitutive skin pigmentation depends on the

amount of melanin and its distribution in that tis-

sue. Melanin is significantly photoprotective and

epidermal cells in darker skin incur less DNA dam-

age than do those in lighter skin. This review

summarizes current understanding of the regulation

of constitutive human skin pigmentation and

responses to UV radiation, with emphasis on phy-

siological factors that influence those processes.

Further research is needed to characterize the role

of skin pigmentation to reduce photocarcinogenesis

and to develop effective strategies to minimize such

risks.

Key words: skin/pigmentation/ultraviolet/photoprotec-

tion/DNA damage/repeated irradiation

Received 23 October 2006, revised and accepted for

publication 14 November 2006

Introduction

The diversity in human skin phenotypes is closely associ-

ated with protection against environmental stresses, in

particular exposure to ultraviolet (UV) radiation. It is well

documented that darker skin is dramatically more resist-

ant to the damaging effects of UV, such as photocarcino-

genesis and photoaging, than is lighter skin (Kaidbey

et al., 1979; Kollias et al., 1991; Montagna and Carlisle,

1991; Tadokoro et al., 2003). Westerhof (2006) recently

reviewed the factors that underlie the differences in skin

pigmentation in humans (and that result in various pig-

mentary disorders) which can be traced back more than

4000 yr. It has only been in the past 200 yr that melano-

cytes have been recognized as the primary source of the

melanin pigment, and only in the past 50 yr that the enz-

ymology underlying pigment biosynthesis has started to

be unraveled. Despite that long and rich history, there

are still major and significant gaps in our understanding

of the biosynthesis, structure(s), role(s) and distribution

of melanin, and the regulation of those processes, in the

skin with regard to its color and function.

Within the past decade, our research groups began a

series of collaborations aimed at defining the types of

melanins produced in different types of skin, their distri-

bution and their role(s) in protection from UV damage,

with the ultimate goal of optimizing photoprotection of

the skin and minimizing the risk of photocarcinogenesis

and photoaging. At the same time, many other groups

have had similar interests and there has been an explo-

sion of information in the literature regarding some of

these important issues. Our studies in this area were

performed according to three distinct clinical protocols

(outlined in Figure 1) and compared the effects of a

single dose (one minimal erythemal dose, MED) or

repeated doses of UV on human skin. The subjects

studied represent six racial/ethnic groups as defined in

(Tadokoro et al., 2003) or six phototypes as defined by

Fitzpatrick (1988). The goal of this review was to sum-

marize current understanding of the regulation of consti-

tutive human skin pigmentation and responses to UV

radiation, with emphasis on physiological factors that

influence those processes. We focus on data for human

skin because that alone is a comprehensive topic. There

is a vast literature available for studies in animal models

and in culture and several recent reviews have covered

those topics (Ha et al., 2005; Noonan et al., 2003; Tyrrell

and Reeve, 2006).�These authors contributed equally to this study

Copyright ª 2006 Blackwell Munksgaard ReviewNo claim to original US government works doi: 10.1111/j.1600-0749.2006.00358.x

2 Pigment Cell Res. 20; 2–13

Regulation of constitutive skinpigmentation

Ultimately, the color of the skin, hair and eyes is deter-

mined by the presence of several major chromophores,

melanin and in some cases, carotenoids and oxy-/deoxy-

hemoglobin (Stamatas et al., 2004). Differences in the

absorption spectra of those compounds allow the meas-

urement of their content as well as characterization of

their up- or down-regulation during physiological and

pathological processes (cf. the role of pigmentation in

photoprotection section below). Melanins are synthes-

ized in different types and amounts by melanocytes

residing in those tissues. In the skin and hair, the

pigment is actively transferred to keratinocytes for

distribution towards the surface of the epidermis or in

hair shafts, thus keratinocytes also play a key role in

determining the pigmentation of those tissues. Szabo

(1954) made the first important observations of the

skin’s pigmentary system about 50 yr ago when they

developed an immunohistochemical approach (using

DOPA as a melanogenic precursor) to stain tissues for

the enzymatic activity of tyrosinase, the critical factor

underlying melanin biosynthesis. They initially examined

Caucasian skin (alternatively called ‘white’ or ‘light’ skin

in some studies) but later extended their studies to

other racial/ethnic skin types (Szabo, 1967; Szabo et al.,

1969). These and other studies (Glimcher et al., 1973;

Rosdahl and Rorsman, 1983; Staricco and Pinkus, 1957)

provided evidence that the densities and distributions of

melanocytes in different types of human skin are relat-

ively similar in comparable areas of the body. They con-

cluded that the large differences in pigmentation

resulted not only from the production of different

amounts of melanins in those tissues but also on their

distribution by neighboring keratinocytes. They coined

the term ‘epidermal melanin unit’ which remains in use

today, although we now understand that other cells in

the epidermis (e.g. Langerhans cells) and dermis (e.g.

fibroblasts) also contribute to the regulation of pigmen-

tary phenotype. Lighter skin has less melanin and what

is produced is typically found arranged in clusters of

melanosomes in keratinocytes while darker skin has

more melanin and the melanosomes are distributed

individually in keratinocytes (thus absorbing light more

efficiently). Szabo’s group also made the interesting

observation that the density of melanocytes in the

epidermis varied according to body location, being the

highest on the upper dorsal skin and lower in other

areas. Those findings were confirmed and expanded by

Whiteman et al. (1999) who examined melanocyte

density in various areas of the body and measured

visible skin pigmentation in an effort to characterize

determinants of melanocyte density. They reported that

pigmentary characteristics, including hair and eye color

as well as degree of tan, were not associated with

melanocyte density in the skin, and they confirmed that

the highest melanocyte density was found in skin on

the back and shoulders, with lower levels at other

anatomical sites. Recent studies reported that the

density of melanocytes in various types of racial/ethnic

skin is virtually identical (Alaluf et al., 2003; Tadokoro

et al., 2003) but that the melanocyte density in skin of

the palms and soles is about 10–20% than that in skin

on the trunk (Yamaguchi et al., 2004).

In our study characterizing determinants of skin pig-

mentation in six distinct racial/ethnic groups, we found

that although the melanocyte density in all types of skin

examined was statistically identical, the amount of mel-

anins detected by immunohistochemical stain, or by

chemical analysis varied greatly and correlated well with

visible pigmentation (Tadokoro et al., 2003). The transfer

of melanin granules to keratinocytes and their subse-

quent distribution in the epidermis is critical to visible

pigmentation. That process remains rather poorly under-

stood at this time, despite intensive efforts to deter-

mine factors that regulate it. Several studies have

A

B

C

D

Figure 1. Summary of clinical protocols used to study ultraviolet

(UV) effects on human skin. (A) Protocol 1: a single one minimal

erythemal dose (MED) dose of UV-A/UV-B on human skin of all

phototypes, as described by Tadokoro et al. (2003). Biopsies were

taken in unexposed skin and at 7 min, 1 day and 7 days after the

UV exposure; (B) protocol 2: five 0.4 MED and five 0.5 MED doses

of solar-simulated radiation (SSR) over the course of 2 weeks,

as described by Schlenz et al. (2005). Biopsies were taken at

unexposed sites and at 3 days after the last SSR treatment

(17 days); (C) protocol 3: repetitive UV-A/UV-B treatment over

3–4 weeks, starting at 0.5 MED and increasing to 3.0 MED, as

described by Miller et al. (2006). Biopsies were taken at unexposed

sites and at weeks 4 and 5 (1 day after the final dose); (D) in all

protocols, the MED for each subject was established using a

graded series of UV doses (shown here on the right side of the

back within the solid box); irradiations and subsequent biopsies

were taken at other sites (shown here on the left side of the back

within the dashed boxes).

Regulation of human skin pigmentation1

Pigment Cell Res. 20; 2–13 3

suggested that melanosome transfer from melanocytes

to keratinocytes is actively regulated by both types of

cells (Minwalla et al., 2001, 2002; Thong et al., 2003;

Virador et al., 2002), and that it can be influenced dra-

matically by environmental stimuli such as UV exposure.

It seems clear that the protease activated receptor-2

(PAR-2)2 receptor expressed on keratinocytes (Babiarz-

Magee et al., 2004; Scott et al., 2003) as well as the

keratinocyte growth factor (KGF)3 (Cardinalli et al., 2005)

play important roles in regulating the transfer of pig-

ment, but much work remains to be performed to more

fully elucidate that process and to determine how it is

regulated physiologically.

Effects of aging on skin pigmentation

As subjects age, their skin and hair pigmentation usually

increases initially until early adulthood after which the

skin often begins to display irregularly pigmented

lesions (hypo- or hyper-pigmented) and the hair often

begins to lose its color (graying). A number of studies

have characterized processes responsible for those

changes. Gilchrest et al. (1979) reported a study in

which they examined skin biopsies taken from sun-

exposed and from sun-protected sites of subjects at

various ages and they characterized parameters involved

with repetitive UV radiation and/or with chronologic

aging (Gilchrest et al., 1979). They found that the den-

sity of melanocytes in the skin was roughly twofold

higher in the UV-exposed sites, but interestingly, they

found that the number of melanocytes decreased

c.10% with each decade of age. Such a decline was

confirmed in subsequent studies by two other groups,

one of which extended those findings to black skin

(Herzberg and Dinehart, 1989; Ortonne, 1990a). Scheib-

ner et al. (1986) reported a study in which they com-

pared skin from Celtic subjects (very fair skin) and

mixed European (Caucasian) subjects (Scheibner et al.,

1986). Interestingly, they found that repetitive exposure

to sunlight led to greater increases in the density of

melanocytes in the darker skin type, but that the density

of Langerhans cells (another minor population in the epi-

dermis) decreased following UV exposure to similar lev-

els in both types of skin. Based on that, they proposed

that the pigment did not provide any protection from

UV, something that is still controversial today, as dis-

cussed below. Stierner et al. (1989) confirmed the

increases in melanocyte density following repetitive UV

exposure, and reported that even in UV-protected sites,

there were increase in melanocyte density (Stierner

et al., 1989). They suggested two interesting outcomes

from their study, i.e. UV exposure might play a role in

melanoma development not only in exposed skin but

also in protected skin, and that infrequent periods of

intensive UV exposure might be more harmful than

regular exposure. Both of those premises seem to be

proving true based on current studies (De Fabo, 2006;

Hearing and Leong, 2005; Noonan et al., 2001, 2003;

Setlow et al., 1993; Wang et al., 2001; Wei et al.,

2003).

Responses of skin pigmentation to UVirradiation

We have performed three clinical studies (Figure 1) that

measured melanocyte density at various times after a

single UV exposure or after repeated UV exposure. Mel-

anocytes were identified in skin biopsies using specific

antibodies to melanocyte-specific markers, such as

tyrosinase, Pmel17, MART1, microphthalmia transcrip-

tion factor (MITF) and dopachrome tautomerase (DCT)4 ,

all of which gave similar results concerning the density

of melanocytes in the epidermis (Figure 2). The sum of

the data show that melanocyte densities in all types of

skin examined begin to increase within 1 week of UV

exposure, but not significantly, despite the fact that vis-

ible tans had developed by that time (Figure 3A). At

3 weeks, and especially at 5 weeks (as seen in our pro-

tocols 2 and 3), the melanocyte density increases signi-

ficantly to levels about threefold higher than in

unirradiated skin.

1. Components of tanning

The induction of skin pigmentation following UV radi-

ation, commonly known as the tanning reaction, has

been recognized for a long time, and occurs not only in

humans, but also in lower species such as fish (Adachi

et al., 2005). However, there is still some controversy

about what processes are involved in this response. In

part this has been due to the fact that erythema of the

skin resulting from UV adds to its visible pigmentation.

It is not simple to separate apparent color due to ery-

thema from that due to melanin pigment, although there

are methods to accomplish that (Stamatas et al., 2004).

There are actually three distinct phases of tanning, two

that occur very quickly (known as the immediate and

persistent tanning reactions), and one that takes more

time to develop [known as the delayed tanning (DT)]

reaction (Figure 4).

2. Immediate and persistent tanning

The immediate tanning reaction, also called immediate

pigment darkening (IPD), occurs within minutes of UV

exposure and persists for several hours (Honigsmann

et al., 1986; Routaboul et al., 1999). Persistent pigment

darkening (PPD) seems to be a distinct second phase of

the tanning reaction; it occurs within hours of UV expo-

sure and persist up to several days (Chardon et al.,

1997; Moyal et al., 2000, 2006). Both IPD and PPD are

thought to result from the oxidation and/or polymeriza-

tion of existing melanin or melanogenic precursors. The

IPD and PPD responses to UV-A are much stronger

than to UV-B. Interestingly, IPD typically appears gray to

black while PPD is tan to brown. Chemical analysis of

Miyamura et al.


Figure 2. Representative staining of skin from the same patient before and after ultraviolet exposure. Stratum corneum and basement

membrane are indicated. (A) Pmel17 (red) at 0 min (left) and 5 weeks (right) – protocol 3. (B) Melanin (black) stained by Fontana–Masson stain

at 0 min (left) and at 5 weeks (right) – protocol 3. (C) Microphthalmia transcription factor (red) at 0 min (left) and at 3 weeks (right) – protocol

2. (D) Tyrosinase (green) at 0 min (left) and at 5 weeks (right) – protocol 3.



skin biopsies taken up to 1 week after UV exposure

shows clearly that relatively little new melanin is pro-

duced within that time frame (Tadokoro et al., 2002,

2003, 2005). Lavker and Kaidbey (1982) proposed that

UV-A could induce pigmentation with little or no latency.

They proposed that this was due to a redistribution of

pre-existing melanosomes in the skin within 18 h post-

irradiation. They noted that the normal distribution of

melanosomes is perinuclear, but that following UV-A

exposure, the melanosomes quickly became more dis-

persed. This led to increased visible pigmentation, an

effect not elicited by UV-B. In fact, this is quite similar

to the phenomenon that occurs in lower species, where

melanins are produced by melanophores, which do not

further distribute the pigment to other cells. Instead,

melanophores retain the melanosomes and effect chan-

ges in pigmentation by redistributing them to the dend-

rites or perinuclear areas (cf. Deacon et al., 2003;

Nascimento et al., 2003). However, Honigsmann et al.

(1986) reported that IPD could be elicited by UV-A in

epidermal sheets. They found that it was not sensitive

to freeze-thawing or formalin fixation, and could not be

blocked by reagents that disrupt the transport machiner-

ies of cells. These results suggested that IPD reflects

the chemical oxidation of existing melanin or melanin

precursors rather than a physiological movement of pig-

ment granules. Joshi et al. (1987) reported that reactive

oxygen species (ROS) were able to oxidize tyrosine and

DOPA to melanin and that this participated in IPD. It

should be noted that ROS are well known to be gener-

ated by UV-A, but much less so by UV-B. Since that

time, it has been generally accepted that the rapid but

transient IPD reflects the promotion of visible light

absorption by melanin or by existing melanogenic pre-

cursors in the skin (Ortonne, 1990b) primarily by oxida-

tion of pre-existing precursors or intermediates

(Routaboul et al., 1999). Ou-Yang et al. (2004) per-

formed an in vivo study which irradiated the dorsal skin

of subjects with UV-A and collected diffuse reflectance

data. They concluded from their results that UV-A induc-

tion of pigmentation depends on soluble melanin and

that two distinct types of absorption by melanins are

involved in UV-A photooxidation. Whether IPD and/or

PPD plays any role in photoprotection against further

immediate UV challenge is currently not known.

3. Delayed tanning and skin thickening

The DT reaction typically takes several days or longer to

develop (Ortonne, 1990b; Young, 2006). Our studies

have shown a wide range in UV sensitivity in individuals

A B

DC

E F

Figure 3. Summary of melanocyte

parameters at various times after

ultraviolet radiation; results from different

protocols were corrected against the

controls for that protocol. Data for 1 day

and 1 week are from protocol 1, data for

3 weeks are from protocol 2, and data for

5 weeks are from protocol 3. (A)

Melanocyte density in melanocytes/mm

skin; data shown are from tyrosinase

staining but comparable results were

obtained when specimens were stained

for microphthalmia transcription factor

(MITF), DCT, MART1, or Pmel17. (B)

Melanin content (Fontana–Masson

staining). (C) Pheomelanin content. (D)

Eumelanin content. (E) MITF staining. (F)

Tyrosinase staining. Data for (B), (E), and

(F) were from ScionImage (Scion Corp,

Frederick, MD, USA)9 ; data for (C) and (D)

were from direct chemical analysis.

Miyamura et al.


with similar skin phenotypes, in the presence and effi-

ciency of their tanning response, and in the persistence

of any tan that develops (Tadokoro et al., 2003, 2005). A

recent study developed a novel method to eliminate the

complicating effects of erythema on the measurement

of melanin pigmentation (Oh et al., 2004). They reported

that skin tanning peaked at 1 week following UV expo-

sure, and then declined over the next 10 weeks,

although not returning to the constitutive level within

that time frame. That same group examined the UV tan-

ning response in Asian skin and reported a relatively

small increase in pigmentation. They concluded that skin

containing lower levels of constitutive pigment had

higher degrees of hyperplasia (skin thickening) and that

this played more of a protective role in UV responses

than did increased pigmentation in lighter skin types

(Hennessey et al., 2005). Long-term increases in skin

pigmentation elicited by UV have been shown to result

from a large number of physiological factors that are

regulated by UV and that affect melanocyte growth and/

or differentiation. Typically those factors are produced

by cells in the skin, including neighboring keratinocytes

and fibroblasts, and even by melanocytes themselves

(for reviews, cf. Gilchrest et al., 1996; Imokawa, 2004;

Kadekaro et al., 2003; Slominski et al., 2004; Sturm,

1998). Interestingly, even products of DNA damage that

result from UV exposure seem to stimulate pigmenta-

tion (Agar and Young, 2005; Eller et al., 1996; Gilchrest

et al., 1996).

4. Melanin content after UV exposure

Two independent groups have reported the dynamics of

melanin synthesis in various types of human skin after

UV exposure. Melanin is produced in two major types

(reviewed in Wakamatsu and Ito, 2002), termed eumela-

nin and pheomelanin. Based on in vitro studies, pheo-

melanin was thought to be detrimental to cells during

UV exposure rather than photoprotective because UV

radiation produced phototoxic byproducts (Schmitz

et al., 1995; Wenczl et al., 1998). However, recent stud-

ies on human skin clearly show that following UV expo-

sure, eumelanin and pheomelanin levels increase slowly

in tandem rather than independently (Hennessy et al.,

2005; Tadokoro et al., 2003; Wakamatsu and Ito, 2006).

This suggests that they are not independently regulated

in human skin, at least by UV. As they occur in relatively

constant proportions, the issue of their potential photo-

toxicity may be a moot point.

Our results of melanin contents in human skin at var-

ious time points after UV radiation (Figures 2B and 3B)

demonstrate clearly that melanin content is not signifi-

cantly affected in human skin of various racial/ethnic ori-

gin within 1 week of a single one MED UV exposure.

Even after 3 weeks of repetitive UV exposure of sub-

jects with phototypes II or III skin, melanin content is

increased only slightly, and not at statistically significant

levels. It is only after 5 weeks that a twofold increase in

melanin content is seen, despite the fact that within

3 weeks, visible tanning of the skin has increased by

fivefold, as measured by a chromameter (Coelho et al.,

2006; Miller et al., 2006). These results are quite consis-

tent with earlier studies by Alaluf et al. (2002a,b) who

reported that the dramatic differences in the pigmenta-

tion of skin of various ethnic origin reflected only about

twofold differences in the chemical content of melanin,

and that the distribution and particle size of melano-

somes were important to visible color. They further

reported that there were only moderate increases (again

less than twofold) in melanin content in repetitively UV-

radiated skin compared with protected skin. The sum of

these results clearly shows that parameters other than

the total amount of melanin are also critical to skin pig-

mentation.

A B

Figure 4. Photographs of tan resulting from acute or repetitive

UV-A/UV-B treatment (protocol 3). Photographs of subjects T01

(red brackets, left) and T35 (red brackets, right) before and at

various times after determination of minimal erythemal dose [acute

ultraviolet (UV), left] and repetitive UV treatment (right). Insets

show threefold magnification of areas outlined by the white boxes,

and demonstrate immediate pigment darkening at day 3 delayed

tanning at day 24, as discussed in the text.



Role of pigmentation in photoprotection

Traditionally, it has been considered that UV-B primarily

affects skin by producing various types of DNA damage,

the two major types being cyclobutane pyrimidine di-

mers (CPD) and 6,4-photoproducts (64PP), while UV-A

mostly causes oxidative damage to proteins, DNA and

membranes (de Gruijl, 2000; Peak and Peak, 1989). It

has been shown that CPDs can also be elicited by UV-A

(Mouret et al., 2006; Zmudzka et al., 1996) and perhaps

it is time to reconsider the strict separation of types of

damage by different wavelengths of UV that is often

assumed. Regardless of the type of UV and the type of

damage involved, there is no dispute that the risk of all

types of skin cancers (melanomas as well as basal and

squamous cell carcinomas) is dramatically higher in ligh-

ter skin types than in darker skin types. This is true for

exposure to natural UV in sunlight and also for UV used

in artificial tanning salons. The study about such risks

(cf. Gallagher et al., 2005; Karagas et al., 2002; Whit-

more et al., 2001; Young, 2004) are common place. The

relationships between skin color, melanin content, race/

ethnicity, and UV-induced DNA damage have been

recently reviewed (Beer and Hearing, in press; Giaco-

moni, 1995; Zeise et al., 1995). In sum, the evidence

suggests that melanin is involved in photoprotection in a

significant way, but not merely as a sunscreen.

Kaidbey et al. (1979) compared black and Caucasian

skin for responses to UV-A and UV-B exposure, using

phototoxicity and erythema as end-points, respectively.

They found that approximately five times as much UV

reaches the upper dermis of Caucasian skin compared

with black skin. They concluded that this was due to

the increased content of melanin, its more efficient dis-

tribution and the thickness of the stratum corneum in

darker skin. However, Ishikawa et al. (1984) performed

a study examining the putative photoprotective role of

epidermal melanin against UV damage and on rates of

DNA repair using guinea pig skin as a model. They com-

pared unscheduled DNA synthesis in black and white

guinea pigs and compared the effects of doses of UV

(at different wavelengths). They found no differences in

DNA repair in the pigmented or unpigmented skin at

any UV dose. They concluded that epidermal melanin

did not significantly protect the DNA of basal cells in

the epidermis against UV irradiation. Guinea pig skin is

an excellent model for human skin with respect to UV

responses. A very recent study showed that responses

to UV decrease with age in guinea pigs, and that age-

associated hyperpigmentation occuring in guinea pig

skin is very similar to processes that occur in human

skin (Tobiishi et al., 2005). Cesarini (1988) reviewed the

issue for the benefit of human skin pigmentation. He

raised the issue, based on chemical and physical analy-

ses of different types of melanins following UV irradi-

ation (cf. Kollias et al., 1991), of whether eumelanins

were less toxic in response to UV exposure compared

with pheomelanins, which are found in relatively higher

proportions in the red-haired sun-sensitive individuals.

Cesarini5 concluded, and Hill et al. (1997) later concurred

(Hill et al., 1997) that the presence of melanin was a

two-edged sword, having beneficial and detrimental

effects on melanocytes/tissues with respect to the

long-term consequences of UV radiation.

A potentially independent issue is whether facultative

pigmentation (i.e. that induced by tanning) provides addi-

tional photoprotection to that provided by constitutive

pigmentation. In that respect, Young et al. (1988) per-

formed a study on type II skin of four volunteers (who

tan poorly) who were treated with or without a sun-

screen and were exposed to 0.7 MED solar-simulated

radiation (SSR) 10 times over a 2-week period. One

week later, a two MED SSR challenge was adminis-

tered and unscheduled DNA synthesis in skin biopsies

was measured, along with melanin content, distribution,

and skin thickness. They concluded that increased mel-

anin content alone was not sufficient to protect fully

against DNA damage and that the use of a sunscreen

was required to lessen DNA damage from SSR. A fol-

low-up study by Young et al. (1991), which examined

skin from subjects of types I–V, extended the original

study and reported that pigmentation and skin thicken-

ing were induced in all types of skin examined. They

concluded that those pigmentation and skin thickening

reduced DNA damage resulting from UV, and that

when combined with use of a sunscreen, improved pro-

tection against subsequent UV challenge. Young and

Sheehan (2001) estimated that melanin has a sun pro-

tection factor (SPF)6 value between 2 and 3, based on its

protective value from erythema and DNA damage.

Kobayashi et al. (1993) revisited this question but

using human skin and monoclonal antibodies that were

specific to different types of DNA damage (CPD and

64PP). In their initial study, they found that melanin con-

tent in human melanoma cells in culture correlated

inversely with DNA damage (CPD and 64PP) following

low doses of UV exposure. Shortly thereafter, the same

group confirmed the photoprotective effects of melanin

against CPD and 64PP in human skin in situ (Kobayashi

et al., 1998). Yet another clinical study reported that tan-

ning offers a ‘modest’ photoprotection against erythema

(Sheehan et al., 1998). The latter study concluded that

while thickening of the stratum corneum improved pro-

tection against UV, the pigment generated had a more

significant effect. Still later, Sheehan et al. (2002)

assessed the rate of DNA repair in considering the con-

sequences of UV exposure of six phototype II volun-

teers and of six phototype IV volunteers. They showed

that the amount of DNA damage was proportional to

the UV dose administered, but reported that rates of

DNA repair were greater in the darker skin. Tadokoro

et al. (2003) examined approximately �80 subjects of

skin phototypes I–VI, showed a close inverse correlation

Miyamura et al.


between melanin content in the skin and the amount of

DNA damage resulting from a given dose of UV. Great

variations in DNA repair were observed which did not

correlate with skin pigment phenotype.

de Winter et al. (2001) performed an interesting study

in which they irradiated healthy volunteers with SSR for

3 weeks, and then treated the tanned skin with a three

MED SSR challenge. They then measured DNA damage

(in the form of CPD) and determined whether the tan-

ning afforded any subsequent protection against UV

damage. In sum, their study concluded that the repetit-

ive UV exposure did increase pigmentation of the skin

and also its thickness, and decreased its sensitivity to

erythema by 75%. There was also an average reduction

in CPD formation by about 60% and they concluded

that the pigmentation induced was photoprotective to

some extent, a conclusion reiterated in a recent review

by Young (2006). Recently, Del Bino et al. (2006) repor-

ted a close correlation between constitutive skin pig-

mentation and UV sensitivity, using sunburn cells as

markers. They noted that the DNA damage was restric-

ted to the upper layers in darker skin but occurred in all

layers in lightly pigmented skin. These results are con-

sistent with data reported by Yamaguchi et al. (2006).

The involvement of the melanocortin 1 receptor

(MC1R) with the regulation of skin and hair pigmentation

is now well documented (cf. Garcia-Borron et al., 2005;

Healy et al., 1999; Rees, 2000; Rees and Flanagan,

1999; Suzuki et al., 1999). The responses and involve-

ment of MC1R with UV-induced skin pigmentation are

quite complex and are regulated at many levels (Rou-

zaud et al., 2005, 2006). Mutations in critical residues in

MC1R elicit the red hair light skin phenotype, which cor-

relates with increased risk for skin cancer. Until very

recently, it was assumed that the skin pigmentation was

the sole factor involved in that risk. However, it is now

becoming quite apparent that MC1R regulates many

other properties of cells on which it is expressed in addi-

tion to pigmentation. Thus much of the protective effect

associated with MC1R function results from its activa-

tion of DNA repair and other anti-photocarcinogenic

activities, as recently reported by several groups (Barnet-

son et al., 2006; Hauser et al., 2006; Kadekaro et al.,

2006). Stimulation of skin pigmentation by activation of

the MC1R (Barnetson et al., 2006) or by bypassing it

when it is mutant (D’Orazio et al., 2006), has now

become an active area to develop agents to artificially

regulate skin pigmentation and increase its photoprotec-

tion from UV damage.

Melanocortin 1 receptor regulates the expression of

melanocyte function primarily via the action of MITF,

which in turn regulates many parameters of melanoblast

and melanocyte function, but most apropos to this art-

icle, it regulates expression of many melanosome-speci-

fic proteins, which directly regulate melanin

biosynthesis. A study by Alaluf et al. (2003) which

examined only the expression of tyrosinase and Tyrp1

in different types of human skin, concluded that expres-

sion of both of those markers were similar in the var-

ious skin types and was increased only moderately by

repetitive UV exposure. Studies by our groups have

examined the expression of those two proteins, as well

as the expression of MITF itself, Pmel17 (a structural

protein involved in melanosome structure) and other

melanocyte-specific markers. The sum of the results of

our studies has shown a specific sequence of changes

in expression of melanocyte markers that is very consis-

tent with the changes in melanin biosynthesis and mel-

anocyte density discussed above. Briefly, expression of

MITF is stimulated relatively quickly after UV exposure

and significant increases are seen as early as 1 day (Fig-

ure 3E). The downstream targets of MITF, e.g. tyrosin-

ase, respond more slowly and are increased slowly over

time, reaching a maximum after 3 weeks (Figure 3F),

which is reasonable based on the kinetics of increases

in MITF expression. Profiles of DCT, TYRP1, and

Pmel17 expression are quite similar to tyrosinase (not

shown). The delay of several weeks before significant

increases in melanin synthesis are induced by UV (Fig-

ure 3B–D) is quite consistent with the time frame of

increases in melanogenic enzymes.

Conclusions and future challenges

In sum, it is clear that melanocyte density is almost

identical in skin of different colors and racial origins, and

that constitutive skin pigmentation depends primarily on

the amount of melanin present and on its distribution.

Melanin most certainly is photoprotective to a significant

degree, and melanocytes in darker skin incur signifi-

cantly less DNA damage than in lighter skin. Interest-

ingly, melanogenic activities increase more efficiently in

darker skin than in lighter skin exposed to comparable

doses of UV.

There are some responses of melanocytes elicited by

UV that occurred in all types of skin examined that fol-

low a consistent and reasonable time course after expo-

sure. Of the melanogenic proteins examined, the

transcription factor MITF (often termed the master regu-

lator of melanocyte function) responds most quickly to

UV (within 1–2 days). The expression of melanosomal

proteins such as tyrosinase, Tyrp1, Pmel17, and DCT is

slower (c.1 week), while increases in melanin synthesis

take a bit longer (c.3 weeks) and increases in melano-

cyte density take even longer (4–5 weeks).

The distribution of melanin in the skin plays an import-

ant role in visible pigmentation and no doubt in photo-

protective capacity. Although, there is an initial surge

(�1 week) in the upward migration of existing pigment

towards the surface of the epidermis, the balance in

pigment distribution is restored by 4–5 weeks when

new synthesis of melanin has been established. It is

clear that relatively small changes in melanin content

and/or distribution can make relatively large changes in



visible pigmentation. Those affect not only constitutive

pigmentation that defines racial/ethnic differences but

also responses to UV exposure.

Surveys of the literature reveal many apparently con-

flicting results and inconsistent conclusions, sometimes

even by the same group. No doubt this is due in large

part to the large number of variables when performing

physiological studies in vivo and in situ. These include

types of UV sources, amounts and frequencies of doses

applied, locations of exposed sites, time points exam-

ined after UV exposure, histories of prior exposure by

subjects, racial/ethnic backgrounds, DNA repair capaci-

ties, and measurement endpoints, among other things.

Important issues that need to be resolved in the

future include defining: (i) whether production of eumel-

anin versus pheomelanin has any consequence on mel-

anocyte function or on photoprotection of the skin; (ii)

whether increased facultative pigmentation provides

added protection against UV damage; (iii) the role of

DNA repair in minimizing long-term damage to the skin

and subsequent photocarcinogenesis; and (iv) the iden-

tity and regulation of UV-induced factors produced in

the skin that are important to modulating its responses

to environmental stress. Given the importance of skin

pigmentation in reducing the risk of photocarcinogene-

sis, further studies are needed to understand the param-

eters critical to photocarcinogenesis and to develop

effective strategies to minimize such risks.

Acknowledgments

This research was supported in part by the Intramural Research

Program of the NIH, National Cancer Institute, Center for Cancer

Research (VJH, SGC, TP, WC, and YY), by the Office of Women’s

Health, the Office of Science and the Center for Devices and

Radiological Health, Food and Drug Administration (SAM, BZZ,

and JZB), by Beiersdorf AG, R&D (RW, CW, and JB) and by

a grant-in-aid for Scientific Research (no. 18591262) from the

Ministry of Education, Culture, Sports, and Technology of Japan

(KW and SI).

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Regulation of human skin pigmentation and responses to ultraviolet radiation

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