Production and utilization of hydrogen peroxide associated with melanogenesis and tyrosinase‐mediated oxidations of DOPA and dopamine

Abstract

Human melanins are heteropolymers synthesized by such diverse cells as those comprising portions of the skin, hair, inner ear, brain and retinal epithelium. These multifunctional pigments are derived from a complex series of enzymatic and nonenzymatic reactions initiated by the hydroxylation of l-phenylalanine to l-tyrosine. This reaction is mediated by the enzyme phenylalanine hydroxylase (EC 1.14.16.1), an iron-containing protein that requires the presence of the cofactor (6R)-l-erythro-5,6,7,8-tetrahydrobiopterin. A critical two-step reaction sequence follows involving the hydroxylation of tyrosine to DOPA (monophenolase activity), and the ensuing oxidation of the o-diphenol (diphenolase activity) to o-quinone (dopaquinone). Subsequent oxidative polymerizations of indolequinones yield brown to black eumelanins, whereas similar reactions involving cysteine and glutathione conjugates of dopaquinone form reddish-brown pheomelanins ( Fig. 1). Neuromelanin, which is also a brown-black pigment, apparently is restricted to the substantia nigra pars compacta and certain other regions of the mammalian brain. The pigment is derived in large part from the oxidation of dopamine (i.e. the decarboxylated derivative of DOPA) with a variety of nucleophiles, including thiols derived from glutathione [1][2][3]. Some of the numerous factors influencing pigment biogenesis in mammalian systems include substrate availability, the presence and concentrations of O 2 , metal ions, thiol The synthesis and involvement of H 2 O 2 during the early stages of melanogenesis involving the oxidations of DOPA and dopamine (diphenolase activity) were established by two sensitive and specific electrochemical detection systems. Catalase-treated reaction mixtures showed diminished rates of H 2 O 2 production during the autoxidation and tyrosinase-mediated oxidation of both diphenols. Inhibition studies with the radical scavenger resveratrol revealed the involvement in these reactions of additional reactive intermediate of oxygen (ROI), one of which appears to be superoxide anion. There was no evidence to suggest that H 2 O 2 or any other ROI was produced during the tyrosinase-mediated conversion of tyrosine to DOPA (monophenolase activity). Establishing by electrochemical methods the endogenous production H 2 O 2 in real time confirms recent reports, based in large part on the use of exogenous H 2 O 2 , that tyrosinase can manifest both catalase and peroxidase activities. The detection of ROI in tyrosinase-mediated in vitro reactions provides evidence for sequential univalent reductions of O 2 , most likely occurring at the enzyme active site copper. Collectively, these observations focus attention on the possible involvement of peroxidase-H 2 O 2 systems and related ROI-mediated reactions in promoting melanocytotoxic and melanoprotective processes.

Melanocytes and Oxidative Stress

“…It results in a continuous generation of ROS all along the process of melanogenesis: H 2 O 2 during its early stages [17] but also during the redox cycling from indoles to quinones [18], hydroxyl radicals and superoxide anion due to the catalytic activity of tyrosinase [19]. In addition, oxidative intermediates including reactive quinones, which are cytotoxic to proteins and DNA in the cells, are generated during melanogenesis [15].…”

Antioxidant Defense and UV-Induced Melanogenesis: Implications for Melanoma Prevention

“…•− ) in melanocytes Mastore et al, 2005). In addition, oxidative intermediates including reactive quinones, which are cytotoxic to proteins and DNA in the cells, are generated during melanogenesis (Ito & Wakamatsu, 2008;Wenczl et al, 1998).…”

“…When the process of melanin production itself can be a crucial source of ROS, on the other hand, the presence of ROS can give rise to abnormal melanogenesis including overproduction of melanin. Previous studies have reported that enhanced ROS/ RNS formation induced by UVR was correlated to elevation of melanogenesis possibly through upregulation of tyrosinase activity, protein and mRNA in melanocytes and/ or melanoma cells (Dong et al, 2010;Horikoshi et al, 2000;Mastore et al, 2005;Yap et al, 2010). In addition, UVA-induced upregulation of heme oxygenase-1 (HO-1) mRNA, a known stress-response gene normally expressed under photooxidative stress, has been shown to associate with stimulation of melanin synthesis in melanocytes (Marrot et al, 2005).…”

Heat Shock Protein Hspa5 Interacts with and Protects Tyrosinase Activity

“…TYR can use O 2-that go into the melanocyte to protect the cell from cytotoxic effect of O 2-usually. However, this balance is broken by either deviant expression or translocation of TYR, which ultimately lead to the exposure of the cells to the attack of O 2- (Mastore et al 2005). Studies have shown that the incidence of Parkinson disease is positively correlated to melanoma.…”