title: A reactive ortho-quinone generated by tyrosinase-catalyzed oxidation of the skin depigmenting agent monobenzone: self-coupling and thiol-conjugation reactions and possible implications for melanocyte toxicity.
abstract: Monobenzone (hydroquinone monobenzylether, 1) is a potent skin depigmenting agent that causes irreversible loss of epidermal melanocytes by way of a tyrosinase-dependent mechanism so far little understood. Herein, we show that 1 can be oxidized by mushroom tyrosinase to an unstable o-quinone (1-quinone) that has been characterized by comparison of its properties with those of a synthetic sample obtained by o-iodoxybenzoic acid-mediated oxidation of 1. Preparative scale oxidation of 1 with tyrosinase and catalytic l-DOPA, followed by reductive workup and acetylation, led to the isolation of two main products that were identified as the acetylated catechol derivative 4 and an unusual biphenyl-type dimer of 4, acetylated 5, arising evidently by coupling of 4 with 1-quinone. In the presence of l-cysteine or N-acetyl-l-cysteine, formation of 4 and 5 was inhibited, and the reaction led instead to monoadducts (6 or 9) and diadducts (7 and 8). A similar behavior was observed when the tyrosinase-promoted oxidation of 1 was carried out in the presence of sulfhydryl-containing peptides, such as reduced glutathione, or proteins, such as bovine serum albumin (BSA), as inferred by detection of adduct 9 by high pressure liquid chromatography-electrochemical detection (HPLC-ED) after acid hydrolysis. The generation and reaction chemistry of 1-quinone described in this article may bear relevance to the etiopathogenetic mechanisms of monobenzone-induced leukoderma as well as to the recently proposed haptenation hypothesis of vitiligo, a disabling pigmentary disorder characterized by irreversible melanocyte loss.
authors.affiliation: Department of Organic Chemistry and Biochemistry, University of Naples Federico II, via Cinthia 4, I-80126 Naples, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Manini
authors.forename: Alessandra
authors.initials: A
authors.lastname: Napolitano
authors.forename: Wiete
authors.initials: W
authors.lastname: Westerhof
authors.forename: Patrick A
authors.initials: PA
authors.lastname: Riley
authors.forename: Marco
authors.initials: M
authors.lastname: d'Ischia
mesh_terms: D000818:Animals; D004156:Catechol Oxidase / Q000191:economics*; D002417:Cattle; D005978:Glutathione; D008544:Melanocytes / Q000187:drug effects; D014442:Monophenol Monooxygenase / Q000378:metabolism*; D011809:Quinones / Q000032:analysis
chemical_list: D011809:Quinones; D004156:Catechol Oxidase; D014442:Monophenol Monooxygenase; D005978:Glutathione