Monobenzone Research Articles

Vitiligo-Inducing Phenols Activate the Unfolded Protein Response in Melanocytes Resulting in Upregulation of IL6 and IL8

Vitiligo is characterized by depigmented skin patches due to loss of epidermal melanocytes. Oxidative stress may play a role in vitiligo onset, while autoimmunity contributes to disease progression. In this study we sought to identify mechanisms that link disease triggers and spreading of lesions. A hallmark of melanocytes at the periphery of vitiligo lesions is dilation of the endoplasmic reticulum (ER). We hypothesized that oxidative stress results in redox disruptions that extend to the ER, causing accumulation of misfolded peptides, which activates the unfolded protein response (UPR). We used 4-tertiary butyl phenol (4-TBP) and monobenzyl ether of hydroquinone (MBEH), known triggers of vitiligo. We show that expression of key UPR components, including the transcription factor X-box binding protein 1 (XBP1), are increased following exposure of melanocytes to phenols. XBP1 activation increases production of immune mediators interleukin-6 (IL6) and IL8. Co-treatment with XBP1 inhibitors reduced IL6 and IL8 production induced by phenols, while over-expression of XBP1 alone increased their expression. Thus, melanocytes themselves produce cytokines associated with activation of an immune response following exposure to chemical triggers of vitiligo. These results expand our understanding of the mechanisms underlying melanocyte loss in vitiligo and pathways linking environmental stressors and autoimmunity.

Is monobenzylether of hydroquinone a safe depigmentation therapy in advanced vitiligo?

Is monobenzylether of hydroquinone a safe depigmentation therapy in advanced vitiligo?

Advanced Treatment Modalities for Vitiligo

Vitiligo is an acquired multifocal and polygenic dyschromia that affects 1% to 3% of the world and presents as multiple depigmented macules and patches. Traditionally, the treatment of vitiligo has focused on pharmacologic interventions, but nearly half of all treated patients fail to respond successfully. Several advanced techniques exist that can aid dermatologists in treating vitiligo in patients who do not respond favorably to traditional pharmacologic treatments. These advanced interventions include the use of the 308-nm excimer laser, total body depigmentation therapy with monobenzyl ether of hydroquinone, microdermabrasion, micropigmentation, khellin-UVA therapy, and surgical management using miniature punch grafting, suction blister grafting, and epidermal cultures. This article reviews the current literature on these advanced treatment modalities for vitiligo and provides a practical guide for application of these techniques. Our ability to treat vitiligo may be imperfect, but through appropriate patient selection and careful application of one or more of these advanced therapies, successful treatment of vitiligo, even in patients refractory to treatment, can be achieved.

Depigmentation therapies in vitiligo

Depigmentation therapy in vitiligo is an option in those with extensive vitiligo who have failed to respond to medical therapy and have obvious cosmetic disfigurement due to intervening patchy pigmented areas. Various aspects of this therapy such as the cost, treatment time, course, permanency of depigmentation, side effects, and the possibility of repigmentation should first be discussed with the patient. At present, there is no ideal depigmenting therapy available, but many agents in the market have been in use for many years. Monobenzyl ether of hydroquinone (MBEH) is the mainstay and Food and Drug Administration (FDA) approved in USA but takes many months to depigment and is associated with local side effects and risk of repigmentation. Other agents which are also used are 4-methoxy phenol and 88% phenol. Physical therapies for depigmentation include Q-switched ruby and alexandrite lasers and cryotherapy. Second-line agents which can be explored for depigmentation include imatinib mesylate, imiquimod, and diphencyprone. Many possible experimental agents are being explored like various phenol derivatives, melanoma vaccines, interferon gamma, busulfan, etc. A major lacuna still exists in this area and a lot more research is desirable to give satisfactory cosmesis to these patients with extensive vitiligo.

Monobenzone as Immunotherapy for Melanoma

The depigmenting agent monobenzone kills melanocytes. We take advantage of this mechanism to depigment nonvitiliginous areas in extensive vitiligo,

Topical application of bleaching phenols; in-vivo studies and mechanism of action relevant to melanoma treatment

Skin depigmentation represents a well-established treatment for extensive vitiligo and may likewise be suited to prevent tumor recurrences and as a prophylactic treatment of familial melanoma, as common bleaching agents are cytotoxic to melanocytes. Effective melanoma prevention requires a bleaching agent-induced loss of exposed melanocytes supported by an immune response to distant pigment cells. Studies on human explant cultures treated with depigmenting agents such as 4-tertiary butyl phenol (4-TBP) or monobenzyl ether of hydroquinone (MBEH) showed a significant increase in the migration of Langerhans cells toward the dermis only upon treatment with MBEH, thus suggesting selective elicitation of an immune response. To assess the depigmenting potential of bleaching agents in vivo, 4-TBP and MBEH were topically applied to C57BL/6 wild type as well as k14-SCF transgenic, epidermally pigmented mice. MBEH-induced significant skin depigmentation in both strains was not observed upon treatment with 4-TBP. Cytokine expression patterns in skin treated with MBEH support activation of a Th1-mediated immune response corresponding to an influx of T cells and macrophages. Importantly, despite insensitivity of tumor cells to MBEH-induced cytotoxicity, significantly retarded tumor growth was observed in B16 challenged k14-SCF mice pretreated with MBEH, likely due to an abundance of cytotoxic T cells accompanied by an increased expression of Th1 and Th17 cytokines. These data support the use of MBEH as a prophylactic treatment for melanoma.

Depigmentation therapies for normal skin in vitiligo universalis

If vitiligo involves most of the body, it might be easier to depigment the normal remaining skin rather than to attempt repigmentation. We reviewed the literature to date regarding available therapies for depigmenting the normal skin in vitiligo universalis. Our review revealed that the threshold regarding what percentage of body surface area qualifies as depigmentation is variable among practitioners. Monobenzyl ether of hydroquinone (MBEH) is the most widely used depigmenting agent and has few side-effects. Tretinoin in combination with MBEH is able to speed depigmentation of the skin. Monomethylether of hydroquinone has also been used successfully for depigmentation. Eighty-eight per cent phenol is also effective in depigmenting the skin but its application on large areas is toxic for liver and kidney. Different types of lasers are also available to destruct the melanocytes selectively, but this technique can be painful and expensive. Cryotherapy is a cheap depigmenting therapy but, because of scarring risk, it should only be used by experienced dermatologists. No trials have compared the efficacy of the above-mentioned well-established depigmentation agents/techniques. Certain drugs such as imatinib, imiquimod and diphencyprone, which are used to treat other diseases, caused depigmentation as a side-effect. Some depigmentation agents used for branding cattle can also serve as topical depigmentation agents. In conclusion, comparative clinical trials are needed to compare the efficacy of various depigmentation agents/techniques. In particular, topical imatinib, imiquimod and diphencyprone may be considered as potential depigmenting agents, which require further investigation. This review revealed that MBEH is safe and effective depigmenting agent.

Application of Monobenzylether of Hydroquinone (MBH) Cream to Normally Pigmented Areas in Patients with Vitiligo, Especially in Persistent Generalized Cases

Application of Monobenzylether of Hydroquinone (MBH) Cream to Normally Pigmented Areas in Patients with Vitiligo, Especially in Persistent Generalized Cases

Monobenzyl Ether of Hydroquinone and 4-Tertiary Butyl Phenol Activate Markedly Different Physiological Responses in Melanocytes: Relevance to Skin Depigmentation

Monobenzyl ether of hydroquinone (MBEH) is a Food and Drug Administration approved drug used for depigmentation therapy of advanced vitiligo. Here, the working mechanism of MBEH is explored in comparison to 4-tertiary butyl phenol (4-TBP), a known causative agent for occupational vitiligo mediating apoptotic melanocytic death. Cytotoxic experiments reveal that similar to 4-TBP, MBEH induces specific melanocyte death. To compare death pathways initiated by 4-TBP and MBEH, classical apoptotic hallmarks were evaluated in treated melanocytes. MBEH induced cell death without activating the caspase cascade or DNA fragmentation, showing that the death pathway is non-apoptotic. Release of High Mobility Group Box-1 protein by MBEH-treated melanocytes and ultrastructural features further confirmed a necrotic death pathway mediated by MBEH. A negative correlation between MBEH-induced cell death and cellular melanin content supports a cytoprotective role for melanin. Moreover, MBEH exposure upregulated the levels of melanogenic enzymes in cultured melanocytes and skin explants, whereas 4-TBP reduced the expression of the same. In summary, exposure to MBEH or 4-TBP has profoundly different consequences for melanocyte physiology and activates different death pathways. As the mode of cell death defines the nature of the immune response that follows, these findings help to explain the relative efficacy of these agents in mediating depigmentation.

A Reactiveortho-Quinone Generated by Tyrosinase-Catalyzed Oxidation of the Skin Depigmenting Agent Monobenzone: Self-Coupling and Thiol-Conjugation Reactions and Possible Implications for Melanocyte Toxicity

Monobenzone (hydroquinone monobenzylether, 1) is a potent skin depigmenting agent that causes irreversible loss of epidermal melanocytes by way of a tyrosinase-dependent mechanism so far little understood. Herein, we show that 1 can be oxidized by mushroom tyrosinase to an unstable o-quinone (1-quinone) that has been characterized by comparison of its properties with those of a synthetic sample obtained by o-iodoxybenzoic acid-mediated oxidation of 1. Preparative scale oxidation of 1 with tyrosinase and catalytic l-DOPA, followed by reductive workup and acetylation, led to the isolation of two main products that were identified as the acetylated catechol derivative 4 and an unusual biphenyl-type dimer of 4, acetylated 5, arising evidently by coupling of 4 with 1-quinone. In the presence of l-cysteine or N-acetyl-l-cysteine, formation of 4 and 5 was inhibited, and the reaction led instead to monoadducts (6 or 9) and diadducts (7 and 8). A similar behavior was observed when the tyrosinase-promoted oxidation of 1 was carried out in the presence of sulfhydryl-containing peptides, such as reduced glutathione, or proteins, such as bovine serum albumin (BSA), as inferred by detection of adduct 9 by high pressure liquid chromatography-electrochemical detection (HPLC-ED) after acid hydrolysis. The generation and reaction chemistry of 1-quinone described in this article may bear relevance to the etiopathogenetic mechanisms of monobenzone-induced leukoderma as well as to the recently proposed haptenation hypothesis of vitiligo, a disabling pigmentary disorder characterized by irreversible melanocyte loss.

Retinoic acid synergistically enhances the melanocytotoxic and depigmenting effects of monobenzylether of hydroquinone in black guinea pig skin

Monobenzylether of hydroquinone (MBEH) has long been utilized for the depigmentation therapy of patients with extensive vitiligo. In this approach, the normally pigmented areas surrounding vitiligo lesions are depigmented to achieve a uniform skin tone. One of the important disadvantages of MBEH therapy, however, is the resistance of a considerable number of vitiligo patients against the depigmenting effect of this agent. We have previously proposed that the glutathione-dependent cytoprotection of melanocytes can be impaired through the inhibition of the enzyme glutathione S-transferase by retinoic acid (RA). The combination of RA with melanocytotoxic agents could thus lead to increased susceptibility of melanocytes to such compounds. In this study we have shown, for the first time, that the melanocytotoxic and depigmenting effects of MBEH are synergistically enhanced when it is combined with RA. The treatment of black guinea pig skin with RA (0.025%) alone induced no significant changes in the number of epidermal melanocytes and no skin depigmentation. On the other hand, MBEH (10%) produced mild to moderate skin depigmentation and reduced the average number of melanocytes from 76 (+/-5)/field (magnification: x 40) in control sites, to 42 (+/-6)/field in the depigmented skin. The RA (0.025%)-MBEH (10%) combination, however, produced a complete degree of depigmentation in the majority of treated sites after 10 days of application and reduced the average number of melanocytes to only 6 (+/-6)/field. RA-MBEH combination serves as a very potent skin depigmenting formula and now awaits future assessments of its potential use for the treatment of extensive vitiligo.

Dermatology Series: Skin of a lighter color

Hypopigmentation is a lessening or lightening of skin color without total depigmentation. Common causes of hypopigmentation are pityriasis alba, a form of non-inflammatory atopic eczema predominantly on the face of children by either race or sun and postinflammatory hypopigmentation. In some countries, the patient may be concerned about the possibility of leprosy. Depigmentation is the total absence of skin color due to loss of melanocytes. This may be posttraumatic such as it may be seen after firm cryosurgery melanocytes are particularly sensitive to killing by cold. Halo naevi are common in adolescence and involve depigmentation around a benign melanocytic naevus with subsequent fading of the naevus. The topical use of monobenzyl ether of hydroquinone as a skin lightening product can cause depigmentation even at sites distant from the application. This patient has vitiligo.

Depigmentation therapy

ABSTRACT: Depigmentation therapy is a treatment option for patients with widespread, treatment-resistant vitiligo. The most commonly employed technique is the application of monobenzylether of hydroquinone (MBEH), also known as monobenzone, to areas with residual pigment. Prior to instituting therapy, the patient must be aware of the cost, treatment time course, risk of distant sites of depigmentation, probable permanency of depigmentation, side effects such as contact dermatitis, and the potential for repigmentation via follicular melanocytes. The social ramifications of depigmentation therapy also must be discussed, especially for patients with skin types IV and V. The sequential use of 4-methoxyphenol and Q-switched ruby laser also has been reported as a successful form of depigmentation therapy.

VITILIGO: Therapeutic Advances

Vitiligo often induces severe cosmetic disfigurement in patients. Both nonsurgical (medical) and surgical approaches for repigmenting vitiliginous macules are described (Table 1). Currently PUVA therapy appears to be the best method in providing reasonable hope for achieving repigmentation. Guidelines for both topical and systemic PUVA are available. Furthermore, surgical graft of autologous epidermal sheet or cultured melanocytes (often combined with keratinocyte co-culture) can be introduced to repigment the depigmented areas where PUVA is ineffective. PUVA therapy after autologous skin graft can enhance the repigmenting efficiency. Although PUVA with or without surgical procedure represents a useful tool in vitiligo treatment, we should look for other new treatment modalities based upon better understanding of basic biology of melanin pigmentation and pathophysiology of this disease. A recent development of topical pseudocatalase and calcium application combined with UVB phototherapy may be one of the typical examples in this respect. Many patients are significantly affected psychologically by the disease. Physicians should attempt to assess the degree of psychological impairment caused by vitiligo. Supportive care should always be offered if necessary in order to minimize these problems appropriately. In closing, normal skin of vitiligo patients can be totally depigmented by monobenzyl ether of hydroquinone in order to match the skin color in certain generalized vitiligo patients. There is a recent case report of extensive vitiligo with rapid repigmentation of depigmenting vitiliginous skin within a few weeks after discontinuing successful depigmentation therapy by monobenzyl ether of hydroquinone.

P-(Benzyloxy)calix[8]arene: One-Pot Synthesis and Functionalization

The condensation of hydroquinone monobenzyl ether in the presence of several bases gives a mixture of cyclic oligomers. Using p-benzyloxyphenol, paraformaldehyde, and NaOH in 45:82:1 molar ratio in...

Dyschromatosis.

The dyschromatoses are a group of disorders characterized by the presence of both hyperpigmented and hypopigmented macules, many of which are small in size and irregular in shape. There are two major forms-dyschromatosis symmetrica hereditaria (DSH) and dyschromatosis universalis hereditaria (DUH), both of which are seen most commonly in Japan. DSH was first described by Toyama in 1929 and is characterized by a symmetrical distribution of hyperpigmented and hypopigmented macules on the extremities, especially over the dorsa of the hands and feet. In 1933, Ichikawa and Hiraga were the first to describe DUH as well-demarcated brown macules admixed with various-sized hypopigmented macules in a generalized as opposed to acral distribution. DUH was noted to appear within the first month of life. Some clinicians have suggested that DSH might be a subtype of DUH; however, we have to wait for the cloning of the causal genes of these diseases before coming to any definite conclusions. The differential diagnosis of dyschromatosis includes xeroderma pigmentosum, dyschromic amyloidosis, and exposure to chemicals such as diphenylcyclopropenone and monobenzyl ether of hydroquinone.

Simultaneous determination of hydroquinone ethers in cosmetics after preconcentration at a carbon paste electrode

A simple electroanalytical method for the simultaneous determination of hydroquinone ethers has been developed using a carbon paste electrode. Hydroquinone (HQ), hydroquinone monobenzyl ether (MBHQ) and hydroquinone dimethyl ether (DMHQ) can be preconcentrated at the electrode surface prior to voltammetric determination. For differential pulse voltammetric measurements with suitable methodical parameters, linear concentrations are found over the ranges 0.07–8.8 mg l–1, 0.13–31.4 mg l–1 and 0.15–33 mg l–1 for HQ, MBHQ and DMHQ, respectively. A comparison is made between the detection limit of platinium, glassy carbon and carbon paste electrodes. The method is applicable to the quantitative determination of hydroquinone ethers in skin lighteners and bleaching creams. The depigmenting agents of bleaching cream in 0.1 mol l–1 phosphate buffer (pH 2.1) have a stripping peak at +0.220, +0.448 and +0.780 V for HQ, MBHQ and DMHQ, respectively. Comparison with results obtained from capillary gas chromatography shows good agreement, to within, on average 2.7%.

Achromic patch test from hydroquinone monobenzyl ether

Achromic patch test from hydroquinone monobenzyl ether

Treatment of nonhairy melanocytic macules by dermabrasion and topical application of 5% hydroquinone monobenzyl ether cream

As showninTable I, the results in patients treated with the full regimen were excellent in 35.3% (Fig. 1), good in 47%, and fair in 17.6%. In contrast, of those patients treated with dermabrasion and topical sunscreen alone, only two of five (40%) had fair results and three of five (60%) had poor results. In those treated with topical HQC and sunscreen only, the results were good in one of two and poor in one of two. No scar formation occurred. Hypopigmentation occurred in only one patient. This may have been caused by excessive use of HQC. Six months after topical HQC wasstopped, the hypopigmentation disappeared.

Influence of Depigmenting Chemical Agents on Hair and Skin Color in Yellow (Pheomelanic) and Black (Eumelanic) Mice

Topical applications of monobenzylether of hydroquinone (MBEH) or intraperitoneal injections of phenol induced graying of hair in eumelanic mice but had little effect on hair color in pheomelanic mice. Amcinonide, an anti-inflammatory agent, elicited whitening of a few hairs in both pheomelanic and eumelanic mice. In phenol-treated eumelanic mice, damaged follicular melanocytes were uprooted from hair bulbs and incorporated into the developing hair. The fate of follicular melanocytes in MBEH- or amcinonide-treated mice was not determined since hair growth and graying were more variable than in phenol-treated mice. In contrast to the susceptibility of eumelanic hair follicles to depigmentation by phenol or MBEH, the tail skin of eumelanic or pheomelanic mice was not depigmented by these agents. Overall, during the 3 week period of treatment that was sufficient for phenol or MBEH to elicit graying of hair, epidermal melanocytes of the tails of eumelanic or pheomelanic mice either failed to respond (phenol) or were stimulated in their "proliferative" and melanogenic activity (MBEH). In contrast, amcinonide brought about a marked reduction in the numbers of DOPA-positive epidermal melanocytes inhabiting the tails of eumelanic or pheomelanic mice. Amcinonide exerted a deleterious influence on the structure and function of tail epidermis. Its actions were partly reversed by simultaneous treatment with MBEH but not with prostaglandin (PGE2).