Monoamine oxidase and catecholamine metabolism

Summary

The enzyme which has come to be known as monoamine oxidase was discovered in liver over 60 years ago as tyramine oxidase (Hare, 1928). Almost 10 years later, Blaschko et al. (1957a,b) established that epinephrine, norepinephrine and dopamine were also substrates for this enzyme. Zeller (1938) distinguished monoamine oxidase as different from several other amine oxidases, such as diamine oxidase. Although it was generally assumed that catecholamines were metabolized by MAO, this was not established until isotopically labelled epinephrine and an MAO inhibitor became available. Schayer (1951) found that after administration of N-methyl-¹⁴C-epinephrine, only about 50% of the radioactivity appeared in the urine, whereas when the ¹⁴C label was incorporated into the β-position on the side chain, almost all of the radioactivity could be recovered. One year later, Zeller et al. (1952) discovered that isonicotinic acid hydrazide (iproniazid) inhibited MAO. When animals pretreated with the MAO inhibitor were administered N-methyl-¹⁴C-epinephrine, almost all of the radioactivity was recovered (Schayer et al., 1955), indicating that the enzyme was responsible for the metabolism of about half of the administered catecholamine. Schayer et al. (1952, 1953) had found that five urinary metabolite products of β-labelled-¹⁴C-norepinephrine could be separated by paper chromatography, but the chemical structures of these compounds were not known.

Armstrong et al. (1957) showed that 3-methoxy-4-hydroxymandelic acid (vanillyl mandelic acid, VMA) was the major metabolite of norepinephrine and Shaw et al. (1957) demonstrated that large amounts of homovanillic acid (HVA) were excreted in urine after administration of 3,4-dihydroxy-phenylalanine (DOPA). These observations led Axelrod to examine the possibility that O-methylation might precede deamination and to his discovery of catechol-O-methyl transferase (Axelrod, 1957, 1959). At that time it became apparent that there were two possible routes for metabolism of norepinephrine to VMA — either deamination followed by O-methylation or O-methylation and subsequent deamination. The relative roles of these two pathways in terminating the physiological actions of catecholamines then became a focus of attention. Biochemical methods were used to access directly the relative importance of the two metabolic pathways. Physiological methods, based on the effects of drugs which alter metabolism of the catecholamine, were used to examine the role of MAO and COMT in terminating the actions of administered or endogenously released catecholamines.