title: Oxidation chemistry of norepinephrine: partitioning of the O-quinone between competing cyclization and chain breakdown pathways and their roles in melanin formation.
abstract: Aberrant oxidation of norepinephrine (1) via the transient o-quinone has been implicated as a critical pathogenetic mechanism underlying the degeneration of noradrenergic cell bodies in the locus coeruleus in Parkinson's disease, the degeneration of noradrenergic nerve terminals in Alzheimer's disease and following transient cerebral ischemia, and the onset and progression of idiopathic vitiligo. An oxidative pathway of 1 is also believed to account for the slow deposition of neuromelanin in pigmented neurons of the locus coeruleus. Remarkably, after extensive investigations spanning over several decades, there is still a lack of knowledge of the oxidation chemistry of 1 beyond the classic cyclization route leading to aminochrome and lutin intermediates. We report herein that oxidation of 1 in the 50-500 microM concentration range with H2O2-dependent oxidizing agents, such as the Fenton reagent (Fe2+-EDTA/H2O2) and the horseradish peroxidase (HRP)/H2O2 system, leads not only to the known cyclization products, such as noradrenochrome and 5,6-dihydroxyindole (3), but also to a significant proportion of chain breakdown products, including 3,4-dihydroxybenzaldehyde, 3,4-dihydroxybenzoic acid, 3,4-dihydroxymandelic acid, and 3,4-dihydroxyphenylglyoxylic acid, which has never been described among the oxidation products or metabolites of 1. Analysis of the brown melanin-like pigment obtained by oxidation of 1 with HRP/H2O2 gave pyrrole-2,3-dicarboxylic acid and pyrrole-2,3,5-tricarboxylic acid, diagnostic markers of 3-derived units in eumelanins. Comparison with reference pigments prepared by similar oxidation of dopamine and 3 indicated that in the case of 1 oxidative polymerization of indole units through the 2-position contributes only to a minor extent to melanin formation. Overall, the results of this study provide a complete characterization of the oxidative chain fission pathways of 1, highlight 3,4-dihydroxyphenylglyoxylic acid as a novel possible metabolic product of this catecholamine, and yield an insight into norepinephrine-melanin, a putative component of locus coeruleus neuromelanin.
authors: Department of Organic Chemistry and Biochemistry, University of Naples Federico II, Italy.
authors: Paola
authors: P
authors: Manini
authors: Lucia
authors: L
authors: Panzella
authors: Alessandra
authors: A
authors: Napolitano
authors: Marco
authors: M
authors: d'Ischia
mesh_terms: D016227:Benzoquinones / Q000737:chemistry*; D003500:Cyclization; D006735:Horseradish Peroxidase / Q000737:chemistry; D006861:Hydrogen Peroxide / Q000737:chemistry; D045563:Indolequinones / Q000737:chemistry; D007211:Indoles / Q000737:chemistry; D007501:Iron / Q000737:chemistry; D008543:Melanins / Q000737:chemistry*; D009638:Norepinephrine / Q000737:chemistry*; D016877:Oxidants / Q000737:chemistry; D010084:Oxidation-Reduction
chemical_list: D016227:Benzoquinones; C045076:Fenton's reagent; D045563:Indolequinones; D007211:Indoles; D008543:Melanins; D016877:Oxidants; C004532:quinone; C088462:noradrenochrome; D006861:Hydrogen Peroxide; D007501:Iron; D006735:Horseradish Peroxidase; D009638:Norepinephrine; C033871:5,6-dihydroxyindole