*3.1.1 Mechanism of action*

*Depigmentation*

universal vitiligo.

**2. Selecting the right candidate**

was to explain the possible mechanism of action for this class of compounds. Tyrosinase was the first suggested target. Also the potential of different phenol derivatives to act as an alternative substrate of the enzyme or as a competitive inhibitor was evaluated. Thus, it was hypothesized that this class of substances, or some of them, may be used for the treatment of skin disorders caused due to hyperpigmentation or melanocyte hyperproliferation. Further structural studies have indicated that the role of the position and type of substitutes in the phenolic ring allow the compound to be hydroxylated or oxidated by tyrosinase [3]. Considering phenol derivatives have a role in this process, hydroquinone was evaluated. Hydroquinone (HQ ) belongs to the phenol/catechol class of chemical agents. Tyrosinase gets inhibited by HQ when interaction occurs with copper at the active site. This further decreases the amount of intracellular glutathione and induces the production of oxygen-reactive species. Thus, HQ acts as an alternative substrate, according to most part of phenol/catechol compounds, because it is similar to tyrosine. The enzyme can thus oxidize HQ without generating the pigment. The quinones produced are able to react with the sulfhydryl residues of the proteins, generating oxidative damage and affecting the cell growth. The depigmenting action is the result of the oxidative damage, involving both lipids and proteins of the cellular membranes. Functional studies have demonstrated that HQ and other phenolic compounds, such as tert-butylphenol, may even act through different mechanisms, including the oxidation of TRP1, and by interfering with RNA and DNA synthesis. HQ has been identified as the main depigmenting agent, whereas among the various phenolic derivatives, the monobenzyl

ether of hydroquinone (MBEH) appeared as the more handful one. In this chapter, we will review and compare various established and potential depigmentation agents as well as emerging therapies that can be used in extensive and

Selection of an appropriate patient is of utmost importance in depigmentation therapy. The option of depigmentation should be made available to only those patients having extensive vitiligo. Detailed and thorough consultation sessions should be conducted with the patient and their families (preferably 2–3 sessions), explaining to them in detail that this therapeutic modality utilizes a potent depigmenting agent and should not be used for cosmetic purposes [2, 3]. They should be explained with all realistic expectations, treatment time frame, the cost involved, and side effects if any, and that once one particular type of treatment is done, they will not be a good candidate for any other type of treatment. Subjects with skin types (V and VI) with a disfiguring contrast between dark-pigmented skin and white vitiliginous areas, especially involving exposed areas (face or the hands), may be a candidate for depigmentation. Moreover, incomplete or trichrome repigmentation (e.g., when using UV light) may cause more disfigurement, thus making such individuals good candidates for depigmentation therapy. The patients should be informed that even after depigmentation, spontaneous repigmentation might occur in vitiligo lesions, warranting additional depigmenting cycles. Patients must be informed that these treatments lead to a definitive irreversible depigmentation. Younger patients with extensive involvement can be given an option of repigmentation instead of opting for depigmentation explaining that complete repigmentation may or may not be achieved. Depigmentation therapy should be avoided in children

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less than 12 years of age [4].

There are multiple pathways through which MBEH causes depigmentation [5]:


There have been reports that when MBEH therapy was combined with all-trans retinoic acid (ATRA), it enhanced depigmentation process and the melanocytotoxic effects via inhibition of the enzyme glutathione S-transferase in melanocytes. This could be a possible way to avoid contact dermatitis when using high concentrations of 40% MBEH. However, combination of ATRA-MBEH did not affect hair pigmentation in animal studies [7].
