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

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, the authors 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 oxidn. of 1. Preparative scale oxidn. 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 deriv. 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 obsd. when the tyrosinase-promoted oxidn. of 1 was carried out in the presence of sulfhydryl-contg. peptides, such as reduced glutathione, or proteins, such as bovine serum albumin (BSA), as inferred by detection of adduct 9 by HPLC-electrochem. detection (HPLC-ED) after acid hydrolysis. The generation and reaction chem. 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.