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Catecholamine Metabolism: a Contemporary View with Implications for Physiology and Medicine

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Catecholamine Metabolism: a Contemporary View with Implications for Physiology and Medicine 0031-6997/04/5603-331–349$7.00 PHARMACOLOGICAL REVIEWS Vol. 56, No. 3 U.S. Government work not protected by U.S. copyright 40301/1169402 Pharmacol Rev 56:331–349, 2004 Printed in U.S.A Catecholamine Metabolism: A Contemporary View with Implications for Physiology and Medicine GRAEME EISENHOFER, IRWIN J. KOPIN, AND DAVID S. GOLDSTEIN Clinical Neurocardiology Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland Abstract ................................................................................ 331 I. Introduction ............................................................................ 331 II. Facts and fallacies ....................................................................... 332 A. Catecholamine deamination ........................................................... 333 B. Formation of vanillylmandelic acid ..................................................... 334 C. Contribution of vesicular leakage to catecholamine metabolism ........................... 335 Downloaded from D. Neuronal and extraneuronal catecholamine metabolism .................................. 336 E. Central and peripheral contributions to norepinephrine metabolism ....................... 337 F. Central and peripheral contributions to dopamine metabolism ............................ 338 III. Clinical implications ..................................................................... 339 A. Neurodegenerative processes .......................................................... 339 B. Neurocirculatory physiology and pathophysiology........................................ 342 pharmrev.aspetjournals.org C. Catecholamine-producing tumors ...................................................... 343 IV. Future perspectives ..................................................................... 345 References .............................................................................. 345 Abstract——This article provides an update about O-methylation consequently leads to production of catecholamine metabolism, with emphasis on correct- 3-methoxy-4-hydroxyphenylglycol, not vanillylman- ing common misconceptions relevant to catechol- delic acid. Vanillylmandelic acid is instead formed in by guest on December 15, 2012 amine systems in health and disease. Importantly, the liver by oxidation of 3-methoxy-4-hydroxyphenyl- most metabolism of catecholamines takes place within glycol catalyzed by alcohol and aldehyde dehydroge- the same cells where the amines are synthesized. This nases. Compared to intraneuronal deamination, extra- mainly occurs secondary to leakage of catecholamines neuronal O-methylation of norepinephrine and from vesicular stores into the cytoplasm. These stores epinephrine to metanephrines represent minor path- exist in a highly dynamic equilibrium, with passive ways of metabolism. The single largest source of meta- outward leakage counterbalanced by inward active nephrines is the adrenal medulla. Similarly, pheochro- transport controlled by vesicular monoamine trans- mocytoma tumor cells produce large amounts of porters. In catecholaminergic neurons, the presence metanephrines from catecholamines leaking from of monoamine oxidase leads to formation of reactive stores. Thus, these metabolites are particularly useful catecholaldehydes. Production of these toxic alde- for detecting pheochromocytomas. The large contri- hydes depends on the dynamics of vesicular-axoplas- bution of intraneuronal deamination to catechol- mic monoamine exchange and enzyme-catalyzed con- amine turnover, and dependence of this on the vesic- version to nontoxic acids or alcohols. In sympathetic ular-axoplasmic monoamine exchange process, helps nerves, the aldehyde produced from norepinephrine is explain how synthesis, release, metabolism, turnover, converted to 3,4-dihydroxyphenylglycol, not 3,4-dihy- and stores of catecholamines are regulated in a coor- droxymandelic acid. Subsequent extraneuronal dinated fashion during stress and in disease states. I. Introduction mitters and hormones that occupy key positions in the regulation of physiological processes and the develop- The catecholamines, dopamine, norepinephrine, and ment of neurological, psychiatric, endocrine, and cardio- epinephrine, constitute a class of chemical neurotrans- vascular diseases. As such, these chemicals and the cat- Address correspondence to: Graeme Eisenhofer, Building 10, echolamine neuronal and endocrine systems in which Room 6N252, National Institutes of Health, 10 Center Dr., MSC- they are produced continue to receive considerable re- 1620, Bethesda, MD 20892-1620. E-mail: [email protected] Article, publication date, and citation information can be found at search attention. http://pharmrev.aspetjournals.org. Because of the long-standing and extensive nature of doi:10.1124/pr.56.3.1. research in the area of catecholamines and catechol- 331 332 EISENHOFER ET AL. amine systems, it should be expected that the pathways nephrine by monoamine oxidase (MAO1) and the subse- of catecholamine metabolism would by now be well un- quent formation of vanillylmandelic acid (VMA), the derstood and clearly described. In fact, almost all text- principal end-product of norepinephrine and epineph- books and most reviews on the subject contain inaccu- rine metabolism (Table 1). Contrary to usual depictions rate and misleading descriptions. As a result, of catecholamine metabolism, VMA is produced mainly by misunderstandings in the area are common and persist. oxidation of 3-methoxy-4-hydroxyphenylglycol (MHPG), Early work on catecholamines centered on their dis- catalyzed by the sequential actions of alcohol and aldehyde position and metabolism. The endogenous cat- dehydrogenases (Kopin, 1985). This pathway is rarely con- echolamines were not easily quantified so that their sidered. Instead, formation of VMA is usually and errone- routes of metabolism were largely deduced from isotopic ously ascribed to sequential oxidative deamination of nor- tracer studies of the fate of exogenously administered epinephrine to form 3,4-dihydroxymandelic acid (DHMA) radiolabeled catecholamines. Pathways of catechol- followed by O-methylation of DHMA to form VMA. This amine metabolism depicted in textbooks and reviews fallacious depiction implies independent sources of MHPG remain based largely on results of these early studies. In and VMA. Indeed, for several years, levels of MHPG in several important respects, those depictions simply do plasma or urine were thought, incorrectly, to provide an not apply and should not be generalized to the sources, index of norepinephrine metabolism in the brain. fate, and significance of endogenous catecholamines and A second area of misunderstanding is that cat- Downloaded from their metabolites. echolamines are usually considered to be metabolized at Subsequent work showed much more complex dynam- sites distant from their sites of synthesis and release, ics, involving multiple processes for catecholamine syn- after their entry into the extracellular fluid or even the thesis, storage, release, inactivation, and metabolism bloodstream. In fact, most metabolism of catecholamines that differ markedly among tissues and cell types, before takes place in the same cells where the amines are and after release of the catecholamines into the extra- produced. Importantly, most of this metabolism occurs pharmrev.aspetjournals.org cellular fluid and circulation. Over the last 20 years, a independently of exocytotic release, and only a small more correct understanding of the disposition and me- fraction of catecholamine metabolites is formed from tabolism of catecholamines has emerged. circulating catecholamines. Failure to recognize these This article reviews and updates current understand- facts probably reflects another misconception that vesic- ing about catecholamine metabolism with emphasis on ular stores of catecholamines exist in a static state until correcting common misconceptions, clarifying how these a stimulus evokes release into the extracellular space. In arose, and outlining the importance of a correct under- fact, vesicular stores of catecholamines exist in a highly standing for advancing progress about catecholamine by guest on December 15, 2012 systems in health and disease. 1Abbreviations: MAO, monoamine oxidase; COMT, catechol-O- methyltransferase; DHMA, 3,4-dihydroxymandelic acid; DHPG, 3,4- dihydroxyphenylglycol; DOPEGAL, 3,4-dihydroxyphenylglycolalde- II. Facts and Fallacies hyde; DOPAC, 3,4-dihydroxyphenylacetic acid; DOPET, 3,4- dihydroxyphenylethanol; DOPAL, 3,4-dihydroxyphenylacetaldehyde; Probably the most common area of misunderstanding MHPG, 3-methoxy-4-hydroxyphenylglycol; VMA, vanillylmandelic concerns the deamination of norepinephrine and epi- acid; HVA, homovanillic acid; CSF, cerebrospinal fluid. TABLE 1 Fallacies and facts about catecholamine metabolism Fallacy Fact Deamination of norepinephrine and epinephrine produces an Deamination of norepinephrine and epinephrine produces a inactive acid metabolite, DHMA reactive aldehyde that is reduced to form DHPG The major pathway of VMA formation is via O-methylation of The major pathway of VMA formation is via oxidation of DHMA formed from deamination of norepinephrine MHPG formed by O-methylation of DHPG Catecholamine stores are static Catecholamine stores are dynamic Most neuronal catecholamines are metabolized after release Most neuronal catecholamines are metabolized intraneuronally after leakage from stores Neuronal catecholamine turnover depends mainly
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