Evidence is presented which indicates that the principal pathway of metabolism of epinephrine in man is O-methylation to metanephrine. The extent of the conLversion to metanephrine, a physiologically inactive compound, indicates that the enzyme responsible for this reaction, catechol-O-methyl transferase, is the enzyme mainly involved in the termination of action of epinephrine in man.

Previous studies indicating the importance of catecholamine metabolism in neuroblastoma were briefly reviewed. Metabolic pathways were presented showing how the major urinary metabolites 3-methoxy-4-hydroxymandelic acid (VMA) and 3-methoxy-4-hydroxy-phenylacetic acid (HVA) are formed from norepinephrine and from dopamine plus 3,4-dihydroxyphenylalanine (DOPA), respectively. For 289 neuroblastoma patients at the time of diagnosis, the urinary excretion of VMA was significantly elevated in 75%, and HVA was elevated in 80%. Periodic assay of these metabolites during the course of the disease revealed that the excretion trends were of prognostic value with 80-90% reliability. By contrast, when the excretion in only the initial urine specimens was considered, the survival rate was the same for patients with normal, and with significantly elevated, excretion. Review of the results of tracer studies aimed at elucidating the in vivo metabolic origins of the urinary metabolites suggested that a) in neuroblastoma, the catecholamines were largely inactivated by intracellular metabolism in the tumor cells; b) there was excess production and excretion of the norepinephrine precursors, DOPA and dopamine; and c) in the tumors of most neuroblastoma patients, the initial enzyme in catecholamine synthesis, tyrosine hydroxylase, had an activity comparable with that in normal adrenal glands. The importance of the metabolism of catecholamines in patients with neuroblastoma was stressed: a) The excretion of elevated levels of urinary catecholamine metabolites were useful in diagnosis and in following the course of the disease, and b) study of the catecholamine metabolism in these patients permitted examination of possible relationships between the activity of the enzymes involved in catecholamine synthesis and the malignancy of this tumor.

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Because of the numerous and important physiological and biochemical actions of epinephrine, the inactivation and metabolism of this and other catechol amines have been the subject of considerable interest, especially in recent years. In 1951 Schayer demonstrated in the urine of rats the presence of four metabolic products of injected C14-epinephrine, but these remained unidentified (1). As recently as 1957 the major pathways and products of catechol amine metabolism were unknown, although it was assumed that the primary route of disposition was mainly by way of oxidative deamination (2, 3).In 1957 Armstrong, McMillan and Shaw identified 3-methoxy-4-hydroxymandelic acid as a major nietabolite of epinephrine and norepinephrine (4). Considering the possible routes of metabolism of the catechol amines in the light of this report, Axelrod sought and demonstrated a new pathway of epinephrine metabolism by 3-0-methylation (5). He showed that 3-0-methyl epinephrine (metanephrine) was formed in vitro when a nonparticulate fraction of rat liver was incubated with epinephrine and S-adenosyl-methionine (5), and that metanephrine was excreted in the urine of rats, both under normal conditions and after the intraperitoneal administration of l-epinephrine bitartrate (5).The magnitude of the 0-methylation pathway in rats was estimated by Axelrod, Inscoe, Senoh and Witkop, They concluded that about 70 per cent of epinephrine was 0-methylated (6). In 1958 a preliminary report was published by LaBrosse, Axelrod and Kety, which indicated that 0-methylation was also the principal route of metabolism of epinephrine in man (7).Earlier studies on epinephrine metabolism in man (7-10) were necessarily limited by insufficient knowledge of the nature of the metabolites, lack of adequate methods for their quantification or incomplete accountability of the excretion of the infused radioactivity, and accurate evaluation of the alternate pathways was not possible. Collection of urine and determination of total radioactivity. Urine was collected without preservative for 1 Prepared by the New England Nuclear Corporation by the reduction of adrenalone with lithium aluminum tritide; labile tritium was removed, and the dlepinephrine-7-H'-d-bitartrate was obtained as a grayishwhite powder. 253

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