Hydroquinone use in dermatology-a review

Colourism, the act of discriminating against a person due to differences in skin colour-has been used to advance and oppress individuals for centuries. The use of skin-bleaching products to obtain lighter skin complexion has skyrocketed over the years. The global skin lightening market is expected to reach $31.2 billion by 2024. A review article detailing about hydroquinone, an efficacious depigmenting agent was recently published in the Indian journal of dermatology venereology and leprology.

Hydroquinone in early years

Hydroquinone or 1,4 dihydroxybenzene was obtained by dry distillation of quinic acid by Pelletier and Caventou in 1820. Natural sources include leaves of several plants and berries in the form of arbutin. Hydrolysis of arbutin gives rise to hydroquinone. Arbutin is also found in coffee beans, teas extracted from berries, broccoli, the bark of the pear tree, red wine, wheat germ and diet cola.

Initially, positive results were seen with mono-benzyl ether of hydroquinone but with further tests, reports of permanent and disfiguring leukoderma became rampant. Currently, monobenzone is used exclusively for depigmenting patients with vitiligo too extensive to re-pigment. Hydroquinone in vitro entirely blocks the formation of melanin when added to a solution containing tyrosinase and tyrosine, the enzyme and substrate required for melanin production. Hydroquinone had no effect on melanin formation by tyrosinase in the presence of dihydroxyphenylalanine (DOPA). Hydroquinone was found to be less effective than monobenzone in reducing normal or abnormal skin colour. Extremely high concentrations of hydroquinone, 10–30%, were noted to deposit a dark substance on the skin produced by auto-oxidation of the molecule. Over a period of few years, more refined or stabilized versions of hydroquinone in 2%, 3% and 5% concentrations were used in studies and histology using haematoxylin eosin and silver nitrate stains confirmed that the quantity of melanin granules in the treated skin was reduced, without any effect on melanocytes.

They also detected perivascular infiltrate in the treated skin and concluded that melanin production reduced to half of normal. Albert Kligman developed a new regimen combining 0.1% tretinoin, 5% hydroquinone and 0.1% dexamethasone into an ointment. Many newer versions containing a varied concentration of the above three ingredients and newer steroids have been introduced since then and found to be effective in 90% of patients with epidermal melanin hyperpigmentation.

Mechanism of action of hydroquinone

In 1965, Arndt and Fitzpatrick proposed that hydroquinone inhibits melanin synthesis. It blocked the formation of melanin by alteration of cellular metabolism. In cell cultures, hydroquinone inhibited the synthesis of DNA and RNA. The inhibition is dependent on the presence and activity of tyrosinase rather than the melanin content of the cell. Thus, hydroquinone is not a useful agent for altering the colour of melanin already deposited within the epidermis or dermis.

It can be used to retard or stop production of new melanin in many conditions such as melasma or post-inflammatory hyperpigmentation.

Study of the auto-oxidation: learning from history!

The earliest studies using 1.5–2% hydroquinone were limited due to auto-oxidation of hydroquinone in the ointment used. The cream used to turn from yellow to dark grey in a few weeks of use. Studies showed that the effectiveness of hydroquinone reduce proportionately with the ease of auto-oxidation. The lower the concentration of hydroquinone in the ointment the lesser chance of oxidation. Strategies like use of stabilizing agents sodium bisulphite and product packing in opaque and smaller tube reduces the oxidation.

Depigmentation caused by hydroquinone is transient and not progressive. It can occur without an inflammation and even at lower concentrations of 2–3%. Depigmentation of the lighter lesions is more conspicuous than the darker ones and hence if treatments are started early for pigmentation dermatoses there is a higher chance of better cosmetic results. Sunlight plays an important role in reducing the effectiveness of hydroquinone and hence sunscreen use is pivotal. Thus it is practical to use sunscreen in the morning and hydroquinone at night for the same reason.

Clinical safety of hydroquinone

The banning of hydroquinone in over-the-counter products in Europe was due to the concerns of ochronosis caused by the over-application of the hydroquinone. It is the duration and the percentage of the hydroquinone used that determines the occurrence of ochronosis. Hydroquinone is safe if used in the proper concentration, with medical prescription and supervision. Hydroquinone is a major metabolic by-product of benzene. Benzene is of known leukaemogenic potential. However, over the last 5 decades, no cases of internal malignancy or skin cancer have been reported secondary to hydroquinone use. The other reported complications of hydroquinone application are irritant or allergic contact dermatitis, postinflammatory hyperpigmentation, hypopigmentation and nail discolouration. Conjunctival melanosis and corneal degeneration have been reported secondary to the atmospheric exposure to hydroquinone in industries.

Thus hydroquinone is one of the best agents in the armamentarium of dermatologists to counter hyperpigmentary disorders though over-the counter use may increase the risks of side effects like ochronosis.

Source- Banodkar PD, Banodkar KP. History of hydroquinone. Indian J Dermatol Venereol Leprol 2022;88:696-9.