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Their mechanisms of action cover (i) tyrosinase inhibition, maturation and enhancement of its degradation; (ii) Mitf inhibition; (iii) downregulation of MC1R activity; (iv) interference with melanosome maturation and transfer; (v) melanocyte loss, desquamation and chemical peeling. Tyrosinase inhibition is the most common approach to achieve skin hypopigmentation as this enzyme catalyses the rate\u2010limiting step of pigmentation. Despite the large number of tyrosinase inhibitors in vitro, only a few are able to induce effects in clinical trials. The gap between in\u2010vitro and in\u2010vivo studies suggests that innovative strategies are needed for validating their efficacy and safety. Successful treatments need the combination of two or more agents acting on different mechanisms to achieve a synergistic effect. In addition to tyrosinase inhibition, other parameters related to cytotoxicity, solubility, cutaneous absorption, penetration and stability of the agents should be considered. The screening test system is also very important as keratinocytes play an active role in modulating melanogenesis within melanocytes. Mammalian skin or at least keratinocytes\/melanocytes co\u2010cultures should be preferred rather than pure melanocyte cultures or soluble tyrosinase.<\/jats:p>","DOI":"10.1111\/j.1600-0749.2006.00334.x","type":"journal-article","created":{"date-parts":[[2006,8,8]],"date-time":"2006-08-08T11:13:20Z","timestamp":1155035600000},"page":"550-571","source":"Crossref","is-referenced-by-count":585,"title":["Hypopigmenting agents: an updated review on biological, chemical and clinical aspects"],"prefix":"10.1111","volume":"19","author":[{"given":"Francisco","family":"Solano","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefania","family":"Briganti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mauro","family":"Picardo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ghanem","family":"Ghanem","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2006,8,8]]},"reference":[{"key":"e_1_2_5_2_1","doi-asserted-by":"crossref","first-page":"1019","DOI":"10.1242\/jcs.114.5.1019","article-title":"The melanocortin 1 receptor is the principal mediator of the effects of agouti signaling on mammalian melanocytes","volume":"114","author":"Abdel\u2010Malek Z.A.","year":"2001","journal-title":"J. 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