Catecholamine Metabolism: From Molecular Understanding to Clinical Diagnosis and Treatment

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Catecholamines are metabolized by multiple pathways involving oxidative deamination catalyzed by monoamine oxidase (MAO), O-methylation by catechol O-methyltransferase (COMT) and conjugation by sulfotransferases or glucuronidases. Aldehyde reductase and aldehyde dehydrogenase are other enzymes that participate in sequence with MAO in the production of respective glycol and acid deaminated metabolites. Additionally, alcohol dehydrogenase contributes to formation of homovanillic acid and vanillylmandelic acid (VMA), the final end-products of catecholamine metabolism. This multiplicity of metabolic enzymes ensures redundancy in the mechanisms of catecholamine inactivation and also leads to a wide array of metabolites. The pathways of metabolism depend on compartmentalization of the catabolic enzymes among different cells and tissues. MAO is the sole metabolizing enzyme present in catecholaminergic neurons. The deaminated metabolite of norepinephrine, dihydroxyphenylglycol (DHPG), provides a marker of intraneuronal metabolism. Differences in metabolism among tissues and organs are considered. VMA, the end-product of norepinephrine and epinephrine metabolism and the predominant metabolite excreted in urine, is produced almost exclusively in the liver, mainly from the deaminated metabolites DHPG and 3-methoxy-4-hydroxyphenylglycol. Intraneuronal metabolism is the main determinant of norepinephrine turnover; most of this is dependent on leakage of transmitter from vesicular stores with the contribution from re-uptake only becoming important with increases in exocytotic release. As illustrated in this chapter, studies of catecholamine metabolism provide an ideal contextural framework for bridging molecular biologic, genetic, neurochemical, psychological, and clinical areas of interest. The chapter details oxidative deamination, O-methylation and conjugation of catechol-O-methyltransferase, glucuronidases, and sulphotransferases, and the catecholamine metabolizing systems. The advances described in this section illustrate how the area of catecholamine metabolism offers an ideal context for bridging basic and clinical areas of research. It can be anticipated that future investigation of catecholamine metabolism will continue to provide the conceptual mortar for cementing together integrative understanding of catecholamine systems in health and disease.