RT Journal Article
SR Electronic
T1 Identification of Quinolines that Inhibit Melanogenesis by Altering Tyrosinase Family Trafficking
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 1576
OP 1586
DO 10.1124/mol.108.050633
VO 74
IS 6
A1 Li Ni-Komatsu
A1 ChunXiang Tong
A1 Guangming Chen
A1 Nelya Brindzei
A1 Seth J. Orlow
YR 2008
UL http://molpharm.aspetjournals.org/content/74/6/1576.abstract
AB A series of quinolines, including chloroquine and quinine, were identified as potent pigmentation inhibitors through screening a compound library in murine melanocytes. Structure-activity relationship analysis indicated that 4-substituted amino groups with a tertiary amine side chain, such as chloroquine, were associated with robust inhibitory activity. In contrast to many previously identified pigmentation inhibitors, these newly identified inhibitors had no effect on either the level or the enzymatic activity of tyrosinase, the rate-limiting enzyme in melanin production. Rather, our results showed that these quinolines inhibited melanogenesis by disrupting the intracellular trafficking of tyrosinase-related proteins and lysosome-associated membrane protein 1 (Lamp-1). In treated melanocytes, tyrosinase and tyrosinase-related protein 1 accumulated in Lamp-1-positive perinuclear organelles instead of melanosomes, thus preventing melanogenesis. The depigmenting abilities of chloroquine and quinine salicylate were assessed in a human skin equivalent model (MelanoDerm). Both compounds were considerably more effective than arbutin, a widely used lightening agent. Our results indicate that quinolines may be useful agents for “cosmeceutical” skin lightening and treatment of hyperpigmentation disorders. The American Society for Pharmacology and Experimental Therapeutics