• Vitiligo;
  • Leukoderma;
  • Phenol;
  • Catechols;
  • Oxidative stress;
  • Apoptosis


  1. Top of page
  2. Abstract
  3. Introduction
  4. Chemical toxins involved in contact/occupational vitiligo
  5. Phenolic and Catecholic Derivatives
  6. Phenol/Catechol Derivative Cytotoxicity in Melanocytes
  7. A Role for oxidative stress in vitiligo
  8. Conclusion
  9. Acknowledgments
  10. References

Vitiligo is an acquired depigmentary disorder of the skin that results from the selective destruction of melanocytes, generally during the second decade of life and affecting approximately 1% of the population worldwide. Loss of cutaneous pigment appears to render the skin susceptible to premature aging and cancer. In addition this disease can be socially devastating for afflicted individuals. The etiology of vitiligo is poorly understood. The present dogma suggests that genetic factors render the melanocyte fragile thus predisposing individuals to developing vitiligo. When subjected to instigating factors, these susceptible, fragile melanocytes undergo apoptosis. Autoimmune factors then perpetuate the removal of the melanocyte component from the skin. In the majority of cases the instigating factors are not known (idiopathic vitiligo), however a small sub-set of individuals develop contact/occupational vitiligo following exposure to particular chemicals. Many of these chemicals have been implicated in both contact/occupational vitiligo and chemical leukoderma. Both conditions present with well-defined, depigmented skin lesions that develop following exposure. Only in the case of vitiligo does the depigmentation spread beyond the areas of contact, probably via an immune-mediated mechanism. The largest class of chemicals known to trigger contact/occupational vitiligo is the phenolic/catecholic derivatives. Many have been demonstrated to be preferentially cytotoxic to melanocytes, with high-dose exposure resulting in the initiation of apoptosis. Phenolic/catecholic derivatives are structurally similar to the melanin precursor tyrosine, and therefore tyrosinase was originally implicated as a mediator of cytotoxicity. However, our data suggests that tyrosinase-related protein-1, rather than tyrosinase, facilitates toxicity, possibly by catalytic conversion of the compounds, which results in the generation of radical oxygen species. The ensuing oxidative stress then triggers activation of cellular free radical scavenging pathways to prevent cell death. Genetic inability of melanocytes to tolerate and/or respond to the oxidative stress may underlie the etiology of contact/occupational vitiligo.

Abbreviations –

4-tertiary butyl phenol


reactive oxygen species


ultraviolet light


  1. Top of page
  2. Abstract
  3. Introduction
  4. Chemical toxins involved in contact/occupational vitiligo
  5. Phenolic and Catecholic Derivatives
  6. Phenol/Catechol Derivative Cytotoxicity in Melanocytes
  7. A Role for oxidative stress in vitiligo
  8. Conclusion
  9. Acknowledgments
  10. References

Skin pigmentation contributes significantly to the health and well-being of an individual. Pigment synthesized by the cutaneous melanocyte protects the individual from various environmental assaults and potential cellular injury that can cause cancer and aging of the skin (1–3). Within the keratinocyte, melanin/melanosomes are preferentially localized over the nucleus (4). In this position, melanin effectively absorbs ultraviolet light (UV) penetrating the skin and prevents consequential DNA damage. In addition, melanin is an effective scavenger of free radicals (5, 6), further protecting the metabolically active keratinocyte that is also under extensive environmental assaults. Lack of epidermal melanin increases susceptibility to skin cancers (1, 2), and is an indicator of aging skin (7). In addition, loss of skin pigmentation can result in compromised cutaneous immunity (8–10) as well as psychological and social problems of self-esteem and personal interactions (11).

Vitiligo is an acquired cutaneous disease in which melanocytes of the skin are destroyed (12–14), resulting in amelanotic lesions of variable size. Generally, vitiligo initially develops on hands, wrists, body folds, and orifices such as eyes, mouth and nose. The onset of vitiligo usually occurs from age 15 to 25, however it can present as early as infancy and as late as the sixth decade of life (15, 16). In some cases the disease is confined to the initial lesions, however, in most cases it progresses and can affect the entire body surface and the eyes. Loss of ocular pigmentation results in photophobia and night blindness (17). Vitiligo lesions can also display a loss in immune response, specifically contact hypersensitivity (8, 9). On the psycho-social level, there are reports of alienation, ostracism, and even suicide in individuals who have lost skin pigmentation as a result of vitiligo (18, 19).

Vitiligo is a multifactorial disease with an etiology that is poorly understood (13, 20–23). The current dogma is that there is a genetic component(s) that renders the melanocyte fragile and susceptible to apoptosis that in turn predisposes individuals to developing the disease. A precipitating factor can more easily induce the fragile melanocyte to initiate programmed cell death or apoptosis when compared with a normal melanocyte. Precipitating factors that have been implicated include sunburn, pregnancy, stress, and exposure to cytotoxic compounds. Common to these precipitating factors is their ability to stimulate melanin synthesis. UV-induced melanocyte-stimulating hormone following overexposure to the sun (24, 25), estrogens during pregnancy (26, 27), cytokines during stress and trauma (i.e. nerve growth factor, neurotrophins, ACTH, endorphins, etc.) (28–32) can all trigger upregulation of melanin synthesis by melanocytes. During biochemical synthesis of melanin, specific quinone and indoles are generated as intermediates. These melanin intermediates can themselves be cytotoxic to melanocytes (33, 34). Therefore, elevated oxidative stress resulting from the increased generation of these intermediates is above the threshold that can be combated by genetically susceptible vitiligo melanocytes and consequently cytotoxicity/cell death is induced. Finally, an autoimmune response can be initiated that facilitates melanocyte removal and perpetuates the disease (35).

There is clearly a multifactorial genetic component to vitiligo, which appears to predispose individuals to this disease (15, 36–38). In one study, individuals with vitiligo were found to have sevenfold more primary family members with vitiligo than expected (15). Vitiligo is not inherited by a simple Mendelian mechanism (39); rather, inheritance patterns demonstrate a complex expression (40–44). A minimum of three diallelic genes might be coordinately involved with the expression of vitiligo (38). A number of genes have recently been implicated in vitiligo, including VIT1 (45), catalase (46), tenascin (47), and FOXD3 (48, 49). Interestingly, these initial candidate genes represent some of the various steps proposed in the complex etiology. The VIT1 gene product has homologies with hMSH6, a G/T mismatch repair gene putatively essential in recovery from DNA damage. Catalase is an endogenous antioxidant essential in combating elevated reactive oxygen species (ROS). Tenascin is an adhesive integrin putatively essential for maintaining the melanocytes on the basement membrane and/or facilitating migration of melanocytes to lesions. The FOXD3 gene maps to an autoimmunity susceptibility locus and encodes a transcription factor putatively de-repressing an autoimmune response.

Although genetic factors predispose an individual to developing vitiligo, a trigger event initiates depigmentation. In the majority of cases this trigger is not known and cases are classed as idiopathic. One distinctive form of vitiligo is contact or occupational vitiligo (13, 20). This form is unique in that its onset correlates with exposure to certain chemicals that induce chemical leukoderma. Contact/occupational vitiligo is distinct from chemical leukoderma in that the initial cutaneous depigmentation extends from the site of chemical contact and subsequently develops into progressive, generalized vitiligo (50).

Chemical toxins involved in contact/occupational vitiligo

  1. Top of page
  2. Abstract
  3. Introduction
  4. Chemical toxins involved in contact/occupational vitiligo
  5. Phenolic and Catecholic Derivatives
  6. Phenol/Catechol Derivative Cytotoxicity in Melanocytes
  7. A Role for oxidative stress in vitiligo
  8. Conclusion
  9. Acknowledgments
  10. References

There is anecdotal and experimental evidence demonstrating that certain environmental chemicals are selectively toxic to melanocytes, both in culture and in vivo (20, 51, 52) and are thus responsible for instigating vitiligo (12, 50). The majority of these toxins are aromatic or aliphatic derivatives of phenols and catechols (Table 1). Some of these compounds have been added to bleaching creams, products used to remove hyperpigmented lesions. Interestingly, these creams are not toxic to melanocytes from all individuals. Even at high dosages only a subset of humans depigment in response to application. In contrast, patients with extensive vitiligo readily depigment following application (J. Nordlund, personal communication). This suggests that these agents are not simple poisons for melanocytes but are injurious only to those genetically susceptible. In addition to phenolic/catecholic derivatives, other chemicals have been shown to precipitate vitiligo. These compounds include sulfhydryls, systemic medications, mercurials, and arsenic (Table 1) (53–60).

Table 1.  Selected chemicals associated with contact/occupational vitiligo
  1. Adapted from Miyamoto and Taylor (23).

Most potent phenol/catechol derivatives
Monobenzyl ether of hydroquinone
Hydroquinone (1,4-dihydroxybenzene; 1,4-benzenediol; quinol; p-hydroxyphenol)
Additional phenol/catechol derivatives
Monomethyl ether of hydroquinone (p-methoxyphenol; p-hydroxyanisole)
Monoethyl ether of hydroquinone (p-ethoxyphenol)
Butylated hydroxytoluene
Butylated hydroxyanisole
Pyrocatechol (1,2-benxenediol)
β-Mercaptoethylamine hydrochloride (cysteamine)
N-(2-mercaptoethyl)-dimethylamine hydrochloride
Sulfanolic acid
Cystamine dihydrochloride
3-Mercaptopropylamine hydrochloride
Cinnamic aldehyde
Benzyl alcohol
Azaleic acid
Optic preparations
 Eserine (physostigmine)
 Diisopropyl fluorophoshate
 Tio-tepa (N, N′, N′′-triethylene-thiophosphoramide)
Systemic medications
 Fluphenazine (prolixin)

Phenolic and Catecholic Derivatives

  1. Top of page
  2. Abstract
  3. Introduction
  4. Chemical toxins involved in contact/occupational vitiligo
  5. Phenolic and Catecholic Derivatives
  6. Phenol/Catechol Derivative Cytotoxicity in Melanocytes
  7. A Role for oxidative stress in vitiligo
  8. Conclusion
  9. Acknowledgments
  10. References

Vitiligo caused by phenolic derivatives was first described by Oliver et al. in 1939 (61). They reported that 25 of 48 (52%) workers using rubber gloves in a leather manufacturing company exhibited depigmentation over their hands and forearms. Patch testing using mono-benzyl ether of hydroquinone, a component in the gloves, caused a positive reaction in affected workers only. Additional reports have subsequently demonstrated contact/occupational vitiligo developing in people working with rubber (62, 63) and industrial oils (64) containing phenolic antioxidants, phenolic germicidal detergents (65), paratertiary-butylphenol containing adhesives (66) and in the general manufacturing of these chemicals. Most individuals affected by these chemicals rapidly develop a vitiligo-like syndrome, while other individuals require years of exposure (63). These observations confirm that there is genetic variability in the response to these environmental contaminants and that melanocytes in vitiligo patients are genetically susceptible to the cytotoxic action of phenolic/catecholic agents. A list of materials containing these phenolic/catecholic derivatives is provided in Table 2 (67, 68).

Table 2.  Materials containing phenolic/catecholic derivatives
Germicidal detergents
Rubber antioxidants
Varnish and lacquer resins
Motor oil additives
Synthetic oils
Duplicating paper
Formaldehyde resins
Soap antioxidants
Latex gloves
De-emulsifiers for oil field use
Printing inks
Valve plants
Photographic chemicals

In addition to effects on the skin, phenolic compounds can damage internal organs. Tertiary butyl phenol (TBP) has induced hepatosplenopathy and diffuse thyroid enlargement among exposed workers (69), while abnormal liver function was found among six individuals with severe TBP-induced leukoderma (70). The NIOSH Criteria Document for a Recommended Standard: Occupational Exposure to Phenol (DHHS-NIOSH Publication No. 76–196) also describes the occurrence of spontaneous abortions, acquired ochronosis, tinnitus, depression, skin cancer, and leukocytosis.

Phenol/Catechol Derivative Cytotoxicity in Melanocytes

  1. Top of page
  2. Abstract
  3. Introduction
  4. Chemical toxins involved in contact/occupational vitiligo
  5. Phenolic and Catecholic Derivatives
  6. Phenol/Catechol Derivative Cytotoxicity in Melanocytes
  7. A Role for oxidative stress in vitiligo
  8. Conclusion
  9. Acknowledgments
  10. References

The mode of action of these compounds on the melanocyte is unconfirmed. Our laboratory began to investigate the etiology of contact vitiligo by initially analyzing the effect of 4-tertiary butyl phenol (4-TBP), a common inducer of vitiligo. 4-TBP is cytotoxic in a dose-dependent manner to cultured human melanocytes (71). We and others have shown that melanocytes are more sensitive than keratinocytes to the cytotoxic effect of 4-TBP (72, 73). This cytotoxicity can be potentiated by cytokines such as basic fibroblast growth factor and alpha-melanocyte stimulating hormone (74). In addition, 4-TBP induces apoptosis, i.e. reorientation of phosphatidylserine in the plasma membrane, DNA fragmentation, and membrane blebbing (72).

Phenols and catechols are structurally similar to tyrosine, the substrate for tyrosinase that initiates the biochemical pathway for melanin synthesis (Fig. 1) (20). Derivatives of phenols and catechols compete with tyrosine for hydroxylation by tyrosinase and interfere with melanin synthesis (34, 75, 76). How this subsequently induced cell death/apoptosis is uncertain. However, semiquinone free radicals generated by the catalytic action of tyrosinase on these phenolic/catecholic derivatives and induction of cell death through peroxidation of membranes has been proposed (52, 77–79). We assessed the role of tyrosinase in mediating the cytotoxicity of 4-TBP and demonstrated that this hypothesis is incorrect. Melanocytes cultured from individuals varying 10-fold in tyrosinase activity levels demonstrated similar dose-dependent cytotoxicity to 4-TBP (72). Melanocytes cultured from oculocutaneous albinism type 1 with null mutations in the gene encoding tyrosinase exhibit similar sensitivities to 4-TBP as normal melanocytes (72). Melanocytes and fibroblasts induced to overexpress tyrosinase via transfection do not demonstrate increased sensitivity to 4-TBP (72). Therefore, tyrosinase does not mediate the effect of 4-TBP. In support of these findings, Picardo et al. found that tyrosinase did not alter sensitivity of cells to catecholic compounds (80).


Figure 1. Chemical structures of the melanin precursor tyrosine and various phenols and catechols implicated in contact/occupational vitiligo.

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We have recently demonstrated that another melanocyte-specific enzyme, i.e. tyrosinase-related protein-1 (Tyrp1), may indeed mediate the action of phenol/catechol derivatives (81). Specifically, transfection of normal Tyrp1 and mutant Tyrp1 will elevate or not affect, respectively, the melanocyte's susceptibility to 4-TBP (Fig. 2). In support of this latter hypothesis, we have demonstrated that Tyrp1 appears to be overexpressed in a cultured line of vitiligo melanocytes (82). Also consistent with this data is that reported by Jimbow et al. (83), which demonstrated that several lines of melanocytes derived from individuals with vitiligo exhibited elevated expression of Tyrp1 accompanied by an extensive cellular distribution as assessed by both immunostaining and Western blot analysis. Therefore, it is possible that Tyrp1 may mediate the cytotoxicity of phenolic/catecholic derivatives by catalyzing their conversion and generating oxygen radicals.


Figure 2. Melanoma cells (IIB) transfected with tyrosinase (IIB-Tyr), Tyrp-1 (IIB-Tyrp1) or a dysfunctional mutant Tyrp1 (IIB-Tyrp1b10), treated with either 100 or 250 μM 4-TBP for 48 h and the viability relative to cells treated with vehicle alone. The results demonstrate that overexpression of Tyrp1 causes significantly increased sensitivity to 250 μM 4-TBP compared with overexpression of either tyrosinase or the mutant form of Tyrp1 (Student's t-test between lines treated with 250 μM 4-TBP. *P < 0.01). Bars represent standard error.

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A Role for oxidative stress in vitiligo

  1. Top of page
  2. Abstract
  3. Introduction
  4. Chemical toxins involved in contact/occupational vitiligo
  5. Phenolic and Catecholic Derivatives
  6. Phenol/Catechol Derivative Cytotoxicity in Melanocytes
  7. A Role for oxidative stress in vitiligo
  8. Conclusion
  9. Acknowledgments
  10. References

The generation of ROS and the inefficiency of cellular mechanisms to combat them are important factors in the pathophysiology of many diseases (84, 85). Melanocytes, like all cell types, are susceptible to oxidative stress. In cells, 4-TBP can undergo enzymatically driven redox-cycling to generate derivatives/intermediates that are capable of inducing oxidative stress. This is based on the evidence that enzymatic redox-cycling of phenol results in the formation of phenoxyl radicals that compromise the anti-oxidant defense mechanisms, resulting in oxidative stress (86). In melanocytes, tyrosinase is involved in the hydroxylation of mono-phenols (e.g. tyrosine) and o-diphenols (e.g. dihydroxyphenylalanine) to o-quinones (87–89). These o-quinones are relatively unstable and undergo non-enzymatic reactions such as cyclization to form aminechrome (87) or addition of a water molecule to generate o-benzoquinones (87, 88). The hydroxylation of 4-TBP by tyrosinase and/or Tyrp1 results in the formation of 4-tertiary butylcatechol, which is subsequently converted to a stable t-butyl-o-benzoquinone (87–89). This reaction requires hydrogen peroxide and results in the generation of peroxides (89). We speculate that exposure of melanocytes to 4-TBP results in the accumulation of peroxides resulting in oxidative stress and cellular damage. We propose that ROS are generated in melanocytes exposed to phenolic/catecholic derivatives and other toxins thus inducing oxidative stress and that vitiligo melanocyte are less capable of combating this oxidative stress. Consistent with this is the observation that patients with vitiligo express elevated levels of H2O2 in their epidermis (90, 91). In addition, autologous reconstructed epidermis from vitiligo patients were more susceptible to in vitro alterations induced by hydrogen peroxide and UVA or UVB irradiation than control cultured skin (92). Vitiligo melanocytes are more susceptible to toxicity induced by exposure to cumene hydroperoxide, an external oxidative stressor (93).

To prevent damage by ROS, cellular antioxidants are activated (94, 95). In addition, antioxidant therapies have been implemented to ameliorate oxidative stress diseases (96–100). Oxidative stress defense mechanisms (i.e. endogenous antioxidants including catalase and apoptotic regulators) may be essential in the response of the vitiligo melanocytes to phenolic/catecholic derivatives in specific, and other inducers of vitiligo in general. Of significance, the epidermis of vitiligo patients express decreased levels of the antioxidant catalase (101), cultured melanocytes derived from patients with vitiligo exhibit significantly lower catalase activity than melanocytes from normal subjects (93) and one of the genes associated with vitiligo encodes catalase (46).

Cells have additional mechanisms of responding to and tolerating various detrimental cellular stressors. These include the expression, interaction, and modulation of the family of Bcl-2 proteins, the regulation of death receptors on the plasma membrane, and a network of caspases and other molecules (102, 103). These pathways may act in tandem with antioxidants to prevent cell death following chemical challenge. One candidate implicated in vitiligo is Bcl-2, a major regulator of apoptosis. Bcl-2 prevents and/or delays the onset of triggered apoptosis in certain cell types by regulating an antioxidant pathway (104). Expression prevents hydrogen peroxide and menadione-induced oxidative cell death (105) suggesting that this protein may play a role in survival following oxidative stress. Bcl-2 is endogenously expressed by melanocytes in the epidermis (106–108). It is also expressed by keratinocytes, the expression being greater in melanocytes compared with keratinocytes (109). Expression is crucial to survival of melanocytes, as Bcl-2 knock-out mice exhibit delayed and progressive pelage hypopigmentation due to loss of melanocytes from the hair bulb, resembling vitiligo (110). We have recently shown that melanocytes from individuals with vitiligo express lower levels of Bcl-2 than melanocytes from normally pigmented individuals (Fig. 3). Thus dysfunction of this crucial anti-apoptotic pathway may contribute to the increased fragility of melanocytes that leads to vitiligo.


Figure 3. Comparison of Bcl-2 expression in normal (A) and vitiligo melanocytes (B) using immunocytochemistry. Normal melanocytes expressed higher levels of the protein. (C) Western blot analysis confirmed that Bcl-2 expression was reduced in two lines of vitiligo melanocytes compared with four lines of control melanocytes.

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  1. Top of page
  2. Abstract
  3. Introduction
  4. Chemical toxins involved in contact/occupational vitiligo
  5. Phenolic and Catecholic Derivatives
  6. Phenol/Catechol Derivative Cytotoxicity in Melanocytes
  7. A Role for oxidative stress in vitiligo
  8. Conclusion
  9. Acknowledgments
  10. References

Understanding the mechanism responsible for the destruction of melanocytes generally and in contact/occupational vitiligo specifically is imperative in light of the sporadic and unpredictable success of current therapies (13, 14). A more important goal is to halt the progression of depigmentation. This likely will require identification of its causes(s) and the development of strategies that prevent melanocyte death. Cellular processes, that when defective appear to result in selective melanocyte death, could include increased synthesis of melanin intermediates and/or ROS, inefficient scavenging of ROS, and/or dysregulation of Bcl-2 and apoptosis. Therefore, future therapeutic designs must focus on correcting the underlying defect in the melanocyte.


  1. Top of page
  2. Abstract
  3. Introduction
  4. Chemical toxins involved in contact/occupational vitiligo
  5. Phenolic and Catecholic Derivatives
  6. Phenol/Catechol Derivative Cytotoxicity in Melanocytes
  7. A Role for oxidative stress in vitiligo
  8. Conclusion
  9. Acknowledgments
  10. References
  • 1
    Stoll HL Jr. Squamous cell carcinoma. In: FitzpatrickTB, EisenAZ, WolffK, FreedbergIM, AustenKF, eds. Dermatology in General Medicine. New York: McGraw-Hill; 1979. p. 362
  • 2
    van Scott EJ. Basal cell carcinoma. In: FitzpatrickTB, EisenAZ, WolffK, FreedbergIM, AustenKF, eds. Dermatology in General Medicine. New York: McGraw-Hill; 1979. p. 377
  • 3
    Gilchrest BA. Skin aging and photoaging: an overview. J Am Acad Dermatol 1989;21: 610613
  • 4
    Boissy RE. Melanosome transfer to and translocation in the keratinocyte. Exp Derm 2003;13: 512
  • 5
    Mason HS, Ingram DJE, Allen B. The free radical property of melanin. Arch Biochem Biophys 1960;86: 225230
  • 6
    Sarna T. Properties and function of the ocular melanin – a photobiophysical view. J Photochem Photobiol B 1992;12: 215258
  • 7
    Gilchrest BA, Blog FB, Szabo G. Effects of aging and chronic sun exposure on melanocytes in human skin. J Invest Dermatol 1979;73: 141143
  • 8
    Uehara M, Miyauchi H, Tanaka S. Diminished contact sensitivity response in vitiliginous skin. Arch Dermatol 1984;120: 195198
  • 9
    Hatchome N, Aiba S, Kato T, Torinuki W, Tagami H. Possible functional impairment of Langerhans cells in vitiliginous skin: reduced ability to elicit dinitrochlorobenzene contact sensitivity reaction and decreased stimulatory effect in the allogeneic mixed skin cell lymphocyte culture reaction. Arch Dermatol 1987;123: 5154
  • 10
    Nordlund JJ. The pigmentary system and inflammation. Pigment Cell Res 1992;5: 362365
  • 11
    Porter JR, Beuf AH, Lerner AB, Nordlund JJ. The effect of vitiligo on sexual relationship. J Am Acad Dermatol 1990;22: 221222
  • 12
    Ortonne J-P, Bose SK. Vitiligo: where do we stand? Pigment Cell Res 1993;6: 6172
  • 13
    Boissy RE, Nordlund JJ. Biology of vitiligo. In: ArndtKA, LeBoitPE, RobinsonJK, WintroubBU, eds. Cutaneous Medicine and Surgery: An Integrated Program in Dermatology. Philadelphia: WB Saunders Company; 1995. pp. 12101218
  • 14
    Le Poole C, Boissy RE. Vitiligo. In: ArndtKA, Le BoitPE, RobinsonJK, WintroubBU, eds. Semin Cutan Med Surg, Vol. 16. Philadelphia: WB Saunders Company; 1997. pp. 314
  • 15
    Nath SK, Majumder PP, Nordlund JJ. Genetic epidemiology of vitiligo: multilocus recessivity cross validated. Am J Hum Genet 1994;55: 981990
  • 16
    Nordlund JJ, Majumder PP. Recent investigations on vitiligo vulgaris. Dermatol Clin 1997;15: 6978
  • 17
    Boissy RE. Extracutaneous melanocytes. In: NordlundJJ, BoissyRE, HearingVJ, KingRA, OrtonneJP, eds. The Pigmentary System. Physiology and Pathophysiology. New York: Oxford University Press; 1998. pp. 5973
  • 18
    Porter J, Beuf A, Nordlund JJ, Lerner AB. Psychological reaction to chronic skin disorders. A study of patients with vitiligo. Gen Hosp Psychiatry 1979;1: 7377
  • 19
    Porter JR, Beuf AH, Lerner A, Nordlund JJ. The psychosocial effect of vitiligo: a comparison of vitiligo patients with ‘normal’ controls, with psoriasis patients, and with patients with other pigmentary disorders. J Am Acad Dermatol 1986;15: 220224
  • 20
    Lerner AB. On the etiology of vitiligo and grey hair. Am J Med 1971;51: 141147
  • 21
    Ortonne J-P, Mosher DB, Fitzpatrick TB. Vitiligo and other hypomelanoses of hair and skin. In: ParrishJA, FitzpatrickTB, eds. Topics in Dermatology. New York: Plenum Medical Book Company; 1983
  • 22
    Le Poole IC, Das PK, van den Wijngaard RM, Bos JD, Westerhof W. Review of the etiopathomechanism of vitiligo: a convergence theory. Exp Dermatol 1993;2: 145153
  • 23
    Miyamoto L, Taylor JS, Chemical leukoderma. In: HannS-K, NordlundJJ, eds. Vitilogo: A Comprehensive Monograph on Basic and Clinical Science. Oxford: Blackwell Science Ltd; 2000. pp. 269280
  • 24
    Scott MC, Suzuki I, Abdel-Malek ZA. Regulation of the human melanocortin 1 receptor expression in epidermal melanocytes by paracrine and endocrine factors, and by UV radiation. Pigment Cell Res 2002;15: 433439
  • 25
    Tsatmali M, Ancans J, Yukitake J, Thody AJ. Skin POMC peptides: their actions at the human MC-1 receptor and roles in the tanning response. Pigment Cell Res 2000;13(Suppl. 8):125129
  • 26
    Grimes PE. Melasma: etiologic and therapeutic considerations. Arch Dermatol 1995;131: 14531457
  • 27
    Kippenberger S, Loitsch S, Solano F, Bernd A, Kaufmann R. Quantification of tyrosinase, TRP-1, and Trp-2 transcripts in human melanocytes by reverse transcriptase-competitive multiplex PCR – regulation by steroid hormones. J Invest Dermatol 1998;110: 364367
  • 28
    Peacocke M, Yaar M, Mansur CP, Chao MV, Gilchrest BA. Induction of nerve growth factor receptors on cultured human melanocytes. Proc Natl Acad Sci U S A 1988;85: 52825286
  • 29
    Gilchrest BA, Park HY, Eller MS, Yaar M. Mechanisms of ultraviolet light-induced melanogenesis. Photochem Photobiol 1996;63: 110
  • 30
    Wakamatsu K, Graham A, Cook D, Thody AJ. Characterization of ACTH peptides in human skin and their activation of the melanocortin-1 receptor. Pigment Cell Res 1997;10: 288297
  • 31
    Slominski A. Identification of beta-endorphin, alpha-MSH and ACTH peptides in cultured human melanocytes, melanoma and squamous cell carcinoma cells by RP-HPLC. Exp Dermatol 1998;7: 213216
  • 32
    Kauser S, Schallreuter KU, Thody AJ, Gummer C, Tobin DJ. Regulation of human epidermal melanocyte biology by beta-endorphin. J Invest Dermatol 2003;120: 10731080
  • 33
    Hochstein P, Cohen G. The cytotoxicity of melanin precursors. Ann N Y Acad Sci 1963;100: 876881
  • 34
    Riley PA. Mechanisms of inhibition of melanin pigmentation. In: NordlundJJ, BoissyRE, HearingVJ, KingRA, OrtonneJ-P, eds. The Pigmentary System. Physiology and Pathophysiology. New York: Oxford University Press; 1998. pp. 401421
  • 35
    Boissy RE. Vitiligo. In: TheofilopoulosAN, BonaCA, eds. The Molecular Pathology of Autoimmunity. Langhorne, PA: Gordon and Breach/Harwood Academic Publishers; 2001. pp. 773780
  • 36
    Hafez M, Sharaf L, El-Nabi SMA. The genetics of vitiligo. Acta Derm Venereol 1983;63: 249251
  • 37
    Majumder PP, Das DK, Li CC. A genetical model for vitiligo. Am J Hum Genet 1988;43: 119125
  • 38
    Majumder P, Nordlund JJ, Nath SK. Pattern of familial aggregation of vitiligo. Arch Dermatol 1993;129: 994998
  • 39
    Lacour JP, Ortonne JP. The genetics of vitiligo. Ann Dermatol Venereol 1995;124: 167171
  • 40
    Kim SM, Chung HS, Hann SK. The genetics of vitiligo in Korean patients. Int J Dermatol 1998;37: 908910
  • 41
    Shah VC, Mojamdar MV, Sharma KS. Some genetic, biochemical and physiological aspects of leucoderma vitiligo. J Cytol Genet Congr 1975;1(Suppl.): 173178
  • 42
    Shah VC, Haribhakti PB, Mojamdar MV, Sharma KS. Statistical study of 600 vitiligo cases in the city of Ahmedabad. Gujarat Med J 1977;42: 5159
  • 43
    Bhatia PS, Mohan L, Pandey ON, Singh KK, Arora SK, Mukhija RD. Genetic nature of vitiligo. J Dermatol Sci 1992;4: 180184
  • 44
    Alkhateeb A, Fain PR, Thody A, Bennett DC, Spritz RA. Epidemiology of vitiligo and associated autoimmune diseases in caucasian probands and their families. Pigment Cell Res 2003;16: 208214
  • 45
    Le Poole IC, Sarangarajan R, Zhao Y, Stennett LS, Brown TL, Sheth P, Miki T, Boissy RE. A novel gene associated with vitiligo. Pigment Cell Res 2001;14: 475484
  • 46
    Casp CB, She JX, McCormack WT. Genetic association of the catalase gene (CAT) with vitiligo susceptibility. Pigment Cell Res 2002;15: 6266
  • 47
    Le Poole IC, van den Wijngaard RM, Westerhof W, Das PK. Tenascin is overexpressed in vitiligo lesional skin and inhibits melanocyte adhesion. Br J Dermatol 1997;137: 171178
  • 48
    Alkhateeb A, Stetler GL, Old W, Talbert J, Uhlhorn C, Taylor M, Fox A, Miller C, Dills DG, Ridgway EC, Bennett DC, Fain PR, Spritz RA. Mapping of an autoimmunity susceptibility locus (AIS1) to chromosome 1p31.3-p32.2. Hum Mol Genet 2002;11: 661667
  • 49
    Alkhateeb A, Fain PR, Fox A, Bennett DC, Spritz RA. FOXD3 promoter variants co-segregate with generalized vitiligo in chormosome IP-linked families. Am J Hum Genet 2003;63(Suppl.):A21
  • 50
    Cummings MP, Nordlund JJ. Chemical leukoderma: fact or fancy. Am J Contact Dermatitis 1995;6: 122127
  • 51
    Bleehen SS, Pathak MA, Hori Y, Fitzpatrick TB. Depigmentation of skin with 4-isopropylcatechol, mercaptoamines and other compounds. J Invest Dermatol 1968;50: 103117
  • 52
    Gellin GA, Maibach HI, Misiaszek MH. Detection of environmental depigmenting substances. Contact Dermatitis 1979;5: 201213
  • 53
    Ito Y, Jimbow K, Ito S. Depigmentation of black guinea pig skin by topical application of cysteaminylphenol, cysteinylphenol, and related compounds. J Invest Dermatol 1987;88: 7782
  • 54
    Sun CC. Allergic contact dermatitis of the face from contact with nickel and ammoniated mercury in spectacle frames and skin-lightening creams. Contact Dermatitis 1987;17: 306309
  • 55
    Bickley LK, Papa CM. Chronic arsenicism with vitiligo, hyperthyroidism, and cancer. N J Med 1989;86: 377380
  • 56
    Yusof Z, Pratap RC, Nor M, Reddy TN. Vogt-Koyanagi-Harada syndrome – a case report. Med J Malaysia 1990;45: 7073
  • 57
    Selvaag E. Chloroquine-induced vitiligo. A case report and review of the literature. Acta Derm Venereol 1996;76: 166167
  • 58
    Levin CY, Maibach H. Exogenous ochronosis. An update on clinical features, causative agents and treatment options. Clin Dermatol 2001;2: 213217
  • 59
    Flickinger CW. The benzenediols: catechol, resorcinol and hydroquinone – a review of the industrial toxicology and current industrial exposure limits. Am Industr Hyg Assoc J 1976;37: 596606
  • 60
    Shelley W. p-Cresol: cause of ink-induced hair depigmentation in mice. Br J Dermatol 1974;90: 169174
  • 61
    Oliver EA, Schwartz L, Warren LH. Occupational leukoderma. JAMA 1939;113: 927928
  • 62
    Quevedo WC Jr, Fitzpatrick TB, Szabo G, Jimbow K. Biology of the melanin pigmentary system. In: FitzpatrickTB, EisenAZ, WolffK, FreedbergIM, AustenKF, eds. Dermatology in General Medicine. New York: McGraw-Hill; 1986. pp. 224251
  • 63
    O'Malley MA, Mathias T, Priddy M, Molina D, Grote AA, Halperin WE. Occupational vitiligo due to unsuspected presence of phenolic antioxidant byproducts in commercial bulk rubber. J Occup Med 1988;30: 512516
  • 64
    Gellin GA, Possick PA, Perone VB. Depigmentation from 4-tertiary butyl catechol – an experimental study. J Invest Dermatol 1970;55: 190197
  • 65
    Kahn G. Depigmentation caused by phenolic detergent germicides. Arch Dermatol 1970;102: 177187
  • 66
    Bajaj AK, Gupta SC, Chatterjee AK. Contact depigmentation from free para-tertiary-butylphenol in bindi adhesive. Contact Dermatitis 1990;22: 99102
  • 67
    Calnan CD. Occupational leukoderma from alkyl phenols. Proc R Soc Med 1973;66: 258260
  • 68
    Gellin G, Maibach H. Detection of environmental depigmenting chemicals. In: MarzulliF, MaibchH, eds. Dermatotoxicology. Washington, DC: Hemisphere; 1983. pp. 443459
  • 69
    Rodermund O-E, Jörgens H, Müller R, Marsteller H-J. Systemische verönderungen bei berufsbedingter vitiligo. Hautarzt 1975;26: 312316
  • 70
    James O, Mayes RW, Stevenson CJ. Occupational vitiligo induced by p-tert-butylphenol: a systemic disease? Lancet 1977;2: 12171219
  • 71
    Yang F, Boissy RE. Effects of 4-tertiary butylphenol (4-TBP) on the tyrosinase activity in human melanocytes. Pigment Cell Res 1999;12: 237245
  • 72
    Yang F, Sarangarajan R, Le Poole IC, Medrano EE, Boissy RE. The cytotoxicity and apoptosis induced by 4-tertiary butylphenol in human melanocytes is independent of tyrosinase activity. J Invest Dermatol 2000;114: 157164
  • 73
    Bowen AR, Hanks AN, Allen SM, Alexander A, Diedrich MJ, Grossman D. Apoptosis regulators and responses in human melanocytic and keratinocytic cells. J Invest Dermatol 2003;120: 4855
  • 74
    Yang F, Abdel-Malek Z, Boissy RE. Effects of commonly used mitogens on the cytotoxicity of 4-tertiary butylphenol to human melanocytes. In Vitro Cell Dev Biol 1999;35: 566570
  • 75
    McGuire J, Hinders J. Biochemical basis for depigmentation of skin by phenol germicides. J Invest Dermatol 1971;57: 256261
  • 76
    Jimbow K, Obata H, Pathak MA, Fitzpatrick TB. Mechanism of depigmentation by hydroquinone. J Invest Dermatol 1974;62: 436449
  • 77
    Mans DRA, Lafleur MVM, Westmijze EJ, Horn IR, Bets D, Schuurhuis GJ, Lankelma J, Retel J. Reactions of glutathione with the catechol, the ortho-quinone and the semi-quinone free radical of etoposide. Consequences for DNA inactivation. Biochem Pharmacol 1992;43: 17611768
  • 78
    Halliwell B, Chirico S. Lipid peroxidation: its mechanism, measurement, and significance. Am J Clin Nutr 1993;57(Suppl. 5):715S725S
  • 79
    Nakagawa Y, Tayama S, Moore G, Moldeus P. Cytotoxic effects of biphenyl and hydroxybiphenyls on isolated rat hepatocytes. Biochem Pharmacol 1993;45: 19591965
  • 80
    Picardo M, Passi S, Nazzaro-Porro M, Breathnach A, Zompetta C, Faggioni A, Riley P. Mechanism of antitumoral activity of catechols in culture. Biochem Pharmacol 1987;36: 417425
  • 81
    Manga P, Sarangarajan R, Ramnath E, Boissy RE. 4-(tert)butylphenol cytotoxicity is mediated by tyrosinase related protein-1. Mol Biol Cell 2002;13S: 306a
  • 82
    Le Poole IC, Yang F, Brown TL, Cornelius J, Babcock GF, Das PK, Boissy RE. Altered gene expression in melanocytes exposed to 4-tertiary butyl phenol (4-TBP): upregulation of the A2b adenosine receptor. J Invest Dermatol 1999;113: 725731
  • 83
    Jimbow K, Chen H, Park JS, Thomas PD. Increased sensitivity of melanocytes to oxidative stress and abnormal expression of tyrosinase-related protein in vitiligo. Br J Dermatol 2001;144: 5565
  • 84
    Kehrer JP. Free radicals as mediators of tissue injury and disease. Crit Rev Toxicol 1993;23: 2148
  • 85
    Darr D, Fridovich I. Free radicals in cutaneous biology. J Invest Dermatol 1994;102: 671675
  • 86
    Shvedova AA, Kommineni C, Jeffries BA, Castranova V, Tyurina YY, Tyurin VA, Serbinova EA, Fabisiak JP, Kagan VE. Redox cycling of phenol induces oxidative stress in human epidermal keratinocytes. J Invest Dermatol 2000;114: 354364
  • 87
    Ros JR, Rodriguez-Lopez JN, Varon R, Garcia-Canovas F. Kinetic study of the oxidation of 4-tert-butylphenol by tyrosinase. Eur J Biochem 1994;222: 449452
  • 88
    Rodriguez-Lopez JN, Ros-Martinez JR, Varon R, Garcia-Canovas F. Calibration of a Clark-type oxygen electrode by tyrosinase-catalyzed oxidation of 4-tert-butylcatechol. Anal Biochem 1992;202: 356360
  • 89
    Jimenez M, Garcia-Carmona F. Hydrogen peroxide-dependent 4-t-butylphenol hydroxylation by tyrosinase – a new catalytic activity. Biochim Biophys Acta 1996;1297: 3339
  • 90
    Schallreuter KU, Moore J, Wood JM, Beazley WD, Gaze DC, Tobin DJ, Marshall HS, Panske A, Panzig E, Hibberts NA. In vivo and in vitro evidence for hydrogen peroxide (H2O2) accumulation in the epidermis of patients with vitiligo and its successful removal by a UVB-activated pseudocatalase. J Invest Dermatol Symp Proc 1999;4: 9196
  • 91
    Rokos H, Beazley WD, Schallreuter KU. Oxidative stress in vitiligo: photo-oxidation of pterins produces H(2)O(2) and pterin-6-carboxylic acid. Biochem Biophys Res Commun 2002;292: 805811
  • 92
    Cario-Andre M, Gauthier Y, Pain C, Taieb A. SP-21 Ex vivo vitiligo vs control melanocyte susceptibility to catecholamines and hydrogen peroxide. Pigment Cell Res 2003;16: 587588
  • 93
    Maresca V, Roccella M, Roccella F, Camera E, Del Porto G, Passi S, Grammatico P, Picardo M. Increased sensitivity to peroxidative agents as a possible pathogenic factor of melanocyte damage in vitiligo. J Invest Dermatol 1997;109: 310313
  • 94
    Kagan VE, Kisin ER, Kawai K, Serinkan BF, Osipov AN, Serbinova EA, Wolinsky I, Shvedova AA. Toward mechanism-based antioxidant interventions: lessons from natural antioxidants. Ann N Y Acad Sci 2002;959: 188198
  • 95
    Beal MF. Oxidatively modified proteins in aging and disease. Free Radic Biol Med 2002;32: 797803
  • 96
    Singh K. Oxidants, antioxidants and diseases – a brief review. Indian J Med Sci 1997;51: 226230
  • 97
    Sevanian A, Hodis H. Antioxidants and atherosclerosis: an overview. Biofactors 1997;6: 385390
  • 98
    Maxwell SR, Lip GY. Free radicals and antioxidants in cardiovascular disease. Br J Clin Pharmacol 1997;44: 307317
  • 99
    Meydani M, Meisler JG. A closer look at vitamin E. Can this antioxidant prevent chronic diseases? Postgrad Med 1997;102: 199201
  • 100
    Dragsted LO. Natural antioxidants in chemoprevention. Arch Toxicol Suppl 1998;20: 209226
  • 101
    Schallreuter KU, Wood JM, Berger J. Low catalase levels in the epidermis of patients with vitiligo. J Invest Dermatol 1991;97: 10811085
  • 102
    Kaufmann SH, Hengartner MO. Programmed cell death: alive and well in the new millennium. Trends Cell Biol 2001;11: 526534
  • 103
    Penninger JM, Kroemer G. Mitochondria AIF and caspases – rivaling for cell death execution. Nature Cell Biol 2003;5: 9799
  • 104
    Hockenbery DM. The bcl-2 gene: a regulator of programmed cell death. In: MihichE, SchimkeRT, eds. Apoptosis. New York: Plenum Press; 1994. pp. 157177
  • 105
    Lee YJ, Chen JC, Amoscato AA, Bennouna J, Spitz DR, Suntharalingam M, Rhee JG. Protective role of Bcl2 in metabolic oxidative stress-induced cell death. J Cell Sci 2001;114: 677684
  • 106
    Klein-Parker HA, Warshawski L, Tron VA. Melanocytes in human skin express bcl-2 protein. J Cutan Pathol 1994;21: 297301
  • 107
    van den Oord JJ, Vandeghinste N, De Ley M, De Wolf-Peeters C. Bcl-2 expression in human melanocytes and melanocytic tumors. Am J Pathol 1994;145: 294300
  • 108
    Plettenberg A, Ballaun C, Pammer J, Mildner M, Strunk D, Weninger W, Tschachler E. Human melanocytes and melanoma cells constitutively express the bcl-2 proto-oncogene in situ and in cell culture. Am J Pathol 1995;146: 651659
  • 109
    Tsujimoto Y, Shimizu S. Bcl-2 family: life or death switch. FEBS Lett 2000;466: 610
  • 110
    Veis DJ, Sorenson CM, Shutter JR, Korsmeyer SJ. Bcl-2-deficient mice demonstrate fulminant lymphoid apoptosis, polycystic kidneys, and hypopigmented hair. Cell 1993;75: 229240