ME,'TABOLISM OF 7-H3-El'INE'HRI1 NIE-d-BLITAiTRltA''ATE IN NORMNAL YOUNG MEN

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 3-0methylation (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. The recent identification of an additional metabolite of epinephrine, 3-methoxy-4-hydroxyphenylglycol, by Axelrod, Kopin and Mann (11), the use or development of improved methods for the separation and estimation of this and other metabolites, and the advantages associated with the use of tritium-labeled epinephrine of high specific activity have warranted a further examination of the metabolites of epinephrine in man.