Perspectives in Pharmacology Sources and Significance of Plasma Levels of Catechols and Their Metabolites in Humans DAVID S. GOLDSTEIN, GRAEME EISENHOFER, and IRWIN J. KOPIN Clinical Neurocardiology Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland Received January 28, 2003; accepted March 18, 2003 ABSTRACT Human plasma contains several catechols, including the cat- echolamines norepinephrine, epinephrine, and dopamine, their precursor, L-3,4-dihydroxyphenylalanine (L-DOPA), and their deaminated metabolites, dihydroxyphenylglycol, the main neu- ronal metabolite of norepinephrine, and dihydroxyphenylacetic acid, a deaminated metabolite of dopamine. Products of me- tabolism of catechols include 3-methoxytyrosine (from L- DOPA), homovanillic acid and dopamine sulfate (from dopa- mine), normetanephrine, vanillylmandelic acid, and methoxyhy- droxyphenylglycol (from norepinephrine), and metanephrine (from epinephrine). Plasma levels of catechols and their metab- olites have related but distinct sources and therefore reflect different functions of catecholamine systems. This article pro- vides an update about plasma levels of catechols and their metabolites and the relevance of those levels to some issues in human health and disease. Near the end of the 19th century, soon after the description of the profound cardiovascular effects of injected adrenal extract and the purification and identification of epinephrine as the vasoactive principal of the adrenal gland, researchers began to develop chemical means to assess activity of what came to be called the sympathoadrenomedullary system. The first chemical method for such measurement was colorimet- ric, based on the unusual susceptibility of epinephrine to oxidize, forming a brownish compound called “adreno- chrome”. Early attempts to measure circulating levels of epinephrine and related compounds chemically failed, mainly because the potency of epinephrine corresponds to very low normal concentrations in the bloodstream. Bioas- says such as used by the great American physiologist, Walter B. Cannon were the first to detect successfully epinephrine release into the circulation. Cannon later developed and ex- ploited a preparation based on the magnitude of the increase in heart rate in animals with denervated hearts; abolition of the increase by adrenalectomy confirmed the hormone’s ad- renal source. Subsequent chemical methods depended on flu- orescence detection (after the trihydroxyindole reaction or ethylenediamine condensation) or radioenzymatic assays (af- ter methylation with S-adenosylmethionine and catechol-O- methyltransferase). Ironically, current sensitive chemical methods using liquid chromatography with electrochemical detection depend on the same catechol oxidation as did the original colorimetric method. For almost the whole of the first half of the last century, epinephrine was the only catecholamine to receive attention. Cannon proposed— erroneously—that epinephrine was not only the main vasoactive hormone released by the adrenal gland but also the chemical messenger released from sympa- thetic nerves. This fit with his concept of a unitary sympa- thoadrenomedullary system, which would help maintain ho- meostasis (a word he coined) during emergencies but would not be necessary in day-to-day life. Fifty years after the discovery of epinephrine, norepinephrine, rather than epi- nephrine, was finally identified as the main sympathetic neurotransmitter regulating the cardiovascular system in mammals. Although the notion of a single, emergency sym- pathoadrenomedullary system remains prominent in current research and practice, it is evident that in many situations Article, publication date, and citation information can be found at http://jpet.aspetjournals.org. DOI: 10.1124/jpet.103.049270. ABBREVIATIONS: DOPA, L-3,4-dihydroxyphenylalanine; DOPAC, dihydroxyphenylacetic acid; DHPG, dihydroxyphenylglycol; ADH, alcohol dehydrogenase; COMT, catechol-O-methyltransferase; DBH, dopamine--hydroxylase; MAO, monoamine oxidase; MHPG, methoxyhydroxyphe- nylglycol; HVA, homovanillic acid; VMA, vanillylmandelic acid; BH 4 , tetrahydrobiopterin; LAAAD, L-aromatic-amino acid decarboxylase; NE, norepinephrine; PST, phenolsulfotransferase; DA, dopamine. 0022-3565/03/3053-800 –811 THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS Vol. 305, No. 3 U.S. Government work not protected by U.S. copyright 49270/1069702 JPET 305:800–811, 2003 Printed in U.S.A. 800 at ASPET Journals on April 3, 2018 jpet.aspetjournals.org Downloaded from