Differential Susceptibilities of Catecholamines to Metabolism by Monoamine Oxidases.

The endogenous catecholamines dopamine (DA), norepinephrine (NE), and epinephrine (EPI) play key roles in neurobehavioral, cardiovascular, and metabolic processes; various clinical disorders; and effects of numerous drugs. Steps in intracellular catecholamine synthesis and metabolism were delineated long ago, but there remains a knowledge gap. Catecholamines are metabolized by two isoforms of monoamine oxidase (MAO), MAO-A and MAO-B, and although the anatomic localization of MAO-A and MAO-B and substrate specificities of enzyme inhibitors are well characterized, relative susceptibilities of the endogenous catecholamines to enzymatic oxidation by MAO-A and MAO-B have not been studied systematically. MAOs catalyze the conversion of catecholamines to catecholaldehydes-3,4-dihydroxyphenylacetaldehyde (DOPAL) from DA and 3,4-dihydroxyphenylglycolaldehyde (DOPEGAL) from NE and EPI. In this study we exploited the technical ability to assay DOPAL and DOPEGAL simultaneously with the substrate catecholamines to compare DA, NE, and EPI in their metabolism by MAO-A and MAO-B. For both MAO isoforms, DA was the better substrate compared to NE or EPI, which were metabolized equally. Since catecholaminergic neurons express mainly MAO-A, the finding that MAO-A is more efficient than MAO-B in metabolizing endogenous catecholamines reinforces the view that the predominant route of intraneuronal enzymatic oxidation of catecholamines is via MAO-A. The results have implications for clinical neurochemistry, experimental therapeutics, and computational models of catecholaminergic neurodegeneration. For instance, the greater susceptibility of DA than the other catecholamines to both MAO isoforms can help explain relatively high concentrations of the deaminated DA metabolite 3,4-dihydroxyphenylacetic acid than of the NE metabolite 3,4-dihydroxyphenylglycol in human plasma and urine. SIGNIFICANCE STATEMENT: Endogenous catecholamines are metabolized by monoamine oxidase (MAO)-A and -B, yielding the catecholaldehydes 3,4-dihydroxyphenylacetaldehyde (DOPAL) from dopamine (DA) and 3,4-dihydroxyphenylglycolaldehyde (DOPEGAL) from norepinephrine (NE) and epinephrine (EPI). Based on measurements of DOPAL and DOPEGAL production, DA is a better substrate than NE or EPI for both MAO isoforms, and MAO-A is more efficient than MAO-B in metabolizing DA, NE, and EPI. MAO-A is the main route of intraneuronal metabolism of endogenous catecholamines. U.S. Government work not protected by U.S. copyright.