Tyrosinase is a copper enzyme, which catalyses both the hydroxylation of monophenols to o-diphenols and the oxidation of o-diquinones to o-quinones. Most whitening agents act specifically to reduce the function of this enzyme by means of the following mechanisms (2): (i) interference with its transcription and/or glycosylation, (ii) inhibition by different modalities, (iii) reduction of by-products, and (iv) post-transcriptional control.
Hydroquinone (HQ), which is a hydroxyphenolic chemical, has been the gold standard for treatment of hyperpigmentation for over 50 years. Its therapeutic efficacy alone or in association with other compounds (3) seems to exert mainly in melanocytes with active tyrosinase activity. HQ may interfere with pigmentation even through: (i) the covalent binding to histidine or interaction with coppers at the active site of tyrosinase, (ii) the inhibition of DNA and RNA synthesis, (iii) the alteration of melanosome formation and melanization extent, and (iv) selectively damaging melanosomes and melanocytes.
The effectiveness of HQ is related directly to the concentration of the preparation. Concentrations of HQ vary from 2% (over the counter) to as high as 10% that are prescribed extemporaneously for resistant cases. It was known that the higher concentrations of HQ were more effective, but the irritating and toxin for melanocytes sign were obvious. There was a reduction in the effectiveness of HQ preparation due to oxidation so that stabilizing agents like sodium bisulphate and ascorbic acid were used as antioxidants. The most suitable vehicle for the formulation is a hydroalcoholic solution (equal parts of propylene glycol and absolute ethanol) or an hydrophilic ointment, or a gel containing 10% alpha-hydroxy acids (AHAs), taking into consideration the desired 3% to 5% HQ concentration in ethanol and propylene glycol 1:1 (or in a cream base or an AHA 10% gel).
The skin lightening effect of HQ can be enhanced by adding various topical agents such as tretinoin and corticosteroids. The following combination has been proposed by Kligman and Willis (5): HQ 5%, tretinoin 0.1%, dexamethasone 0.1%, in ethanol and propylene glycol 1:1 or in hydrophilic ointment. In this formula, tretinoin stimulates the cell turnover promoting the rapid loss of pigment via epidermopoieses, and acts as a mild irritant facilitating the epidermal penetration of HQ and as an antioxidant preventing the oxidation of HQ. Corticosteroids can eliminate the irritation caused by HQ and/or tretinoin (6).
Depigmentation of HQ preparation begins within three weeks after twice-daily application and it is used for a maximum of five to seven weeks. The formulation without antioxidants should never be more than 30 days old. A slight modification of the Kligman and Willis formula is the following: HQ 4%, tretinoin 0.05%, fluocinolone acetonide
0. 01% (or hydrocortisone 1%), in ethanol and propylene glycol 1:1 or in hydrophilic ointment. In this formulation the concentration of tretinoin is lowered to 0.05%, and the aim is to minimize the irritation caused by tretinoin and eliminates local steroid side effects (7). The improvement rate of melasma was ranging from 40% to 87.5% in two to four months.
The side effects of HQ include allergic contact dermatitis, irritant contact dermatitis (more probable with the higher concentrations), and post-inflammatory hyperpigmentation and nail discoloration. Irritation, stinging, and/or burning were observed transiently during the first day of application and disappeared with use of the medication after a few days.