Hyperpigmentary disorders of the skin such as melasma,
age spots, and solar lentigines result from excessive
epidermal melanin synthesized by cutaneous melanocytes.1 Thus, the unique biochemical pathway of melanogenesis
provides a mechanism for developing pharmacologic
regulators of pigmentation. Since its introduction for clinical use in 1961, hydroquinone (HQ) has been a successful tyrosinase
inhibitor for treating hyperpigmentation.2 However, HQ can be metabolized by tyrosinase into toxic oxidation products, causing oxidative damage to the cell and inducing melanocyte death.3 As an alternative, deoxyArbutin (dA) and its second-generation derivatives, deoxyFuran (dF), 2-fluorodeoxyArbutin (fdA), and thiodeoxyArbutin (tdA), are considered to be promising
skin-lightening agents because they inhibit melanogenesis at lower concentrations compared with HQ.4 We have compared
toxicity profiles of dA and its derivatives with that of HQ, aiming to develop an effective therapeutic tyrosinase inhibitor that simultaneously exhibits minimal cytotoxicity.
Phenolic/catecholic derivatives that are structurally similar to the melanin precursor tyrosine can exhibit melanocyte-specific cytotoxicity by interacting with melanogenic enzymes to produce
reactive quinones and reactive oxygen species (ROS).5 The reactive quinones undergo intracellular covalent binding with crucial nucleophilic thiol groups in proteins essential for cell survival.6 ROS generation can induce oxidative stress, ultimately
inducing apoptosis.7 For cellular protection, oxidative stress induced by phenolic compounds can also trigger activation of an intricate arsenal of antioxidants. These antioxidants (superoxide
dismutase [SOD], catalase, glutathione peroxidase, and thioredoxin) serve to scavenge and/or detoxify reactive oxygen intermediates or block free-radical chain reactions (tocopherol) to prevent cell death.8 Catalase is one of the primary defense molecules against oxidative stress. Cellular expression levels of catalase may be a useful marker of both acute and chronic oxidative stress9 because of its ability to neutralize hydrogen peroxide and thus lower ROS concentrations.
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