SKIN-LIGHTENING COSMETIC INGREDIENTS 45 The fi rst three stages are completely controlled genetically, while the next four stages are targets for manipulation through skin-lightening agents. The most important factor other than inheritance affecting skin pigmentation is ultraviolet (UV) radiation (Figure 2). Exposure to UV triggers the following reactions that cause darkening of the skin (13–15): (a) Oxidation and polymerization of melanin (b) Redistribution of melanosomes (c) Activation of MITF (microphthalmia-associated transcription factor) leading to increased melanin content (d) Increase in expression of α-MSH (melanocyte-stimulating harmone) leading to enhanced melanocyte responses (e) Transfer of melanin from the lower to the upper epidermis to prevent damage from radiation A very effective method of reducing UV-induced pigmentation would be to incorporate sunscreens in the vehicle used for skin lightening. Physical sunscreens like zinc oxide and titanium oxide are available to suit delivery vehicles like creams, lotions, gels, etc. Chem- ical sunscreens may be chosen from a variety of synthetic compounds such as ethyl hexyl methoxy cinnamate, butyl methoxydibenzoylmethane, phenyl benzimidazole sulfonic acid, and other substituted salicylates. SKIN LIGHTENING Skin-lightening agents are those that cause depigmenting activity on human skin, and they have been widely used in dermatology and cosmetics. A huge number of actives (both from biological sources and synthetic chemical compounds) have been reported in the literature (16,17). Their mechanism of action is generally through: (a) Tyrosinase inhibition (b) Mitf inhibition (c) Down regulation of MC1R activity Figure 2. Schematic representation of the effect of UV rays on skin leading to pigmentation.

JOURNAL OF COSMETIC SCIENCE 46 (d) Interference with melanosome maturation and transfer (e) Melanocyte loss, exfoliation Successful treatments mostly combine two or more modes of action to achieve a synergis- tic effect. CLASSIFICATION OF SKIN-LIGHTENING INGREDIENTS Skin-lightening ingredients can also be classifi ed by their source, such as the classes to which they belong. The important classes are: (i) Chemical tyrosinase inhibitors (hydroquinone and similar type of compounds) (ii) Botanicals (essentially from plants and algae) (iii) Anti-oxidants (iv) Vitamins—A, B, C, E (v) Peptides (vi) Alpha and beta hydroxyl acids and derivatives TYROSINASE INHIBITION The inhibition of tyrosinase is the most widely reported screening method in the litera- ture for skin-lightening ingredients. Tyrosinase is a copper-containing enzyme present in melanocytes that catalyzes the production of melanin. The biosynthetic pathway of mela- nin synthesis was fi rst elucidated by Raper (18). Tyrosinase inhibition may be achieved by inhibitors from chemical or biological sources. (i) Chemical tyrosinase inhibitors (Figure 3). There has been tremendous activity in the iden- tifi cation of tyrosinase inhibitors that are of synthetic origin. Such compounds are gener- ally highly pure and potent. Synthetic compounds of various classes like hydroquinone and derivatives, phenolic amines, coumarins, chalcone analogs, hydroxy stilbene deriva- tives, benzaldehyde analogs, biphenyls, and trihydroxy fl avones have been studied for their tyrosinase inhibitory properties (21–33). However, many of these compounds have been screened through in vitro assays and their effi cacy and adverse effects need to be established through clinical trials. Chemical com- pounds with depigmenting activity have been used in cosmetics for a long time. Some of the best known tyrosinase inhibitors are hydroquinone, kojic acid, and similar types of compounds. (a) HYDROQUINONE AND DERIVATIVES. Hydroquinone is considered to be the gold standard for depigmenting agents. Hydroquinone interacts with copper at the active site of the en- zyme tyrosinase, thus decreasing its activity by nearly 90% (34). It not only limits ty- rosinase but also oxidizes membrane lipids and proteins through generation of reactive oxygen species (35). The radicals generated inhibit cellular metabolism by affecting DNA and RNA synthesis (36). It is generally administered at concentrations ranging from 1.5% to 5% concentration. The use of hydroquinone in cosmetics has diminished because of adverse side effects due to its cytotoxic nature. Monobenzyl ether of hydroquinone