Evolving views of the metabolic fate of norepinephrine

The metabolic fate of norepinephrine, which is a neurotransmitter in brain as well as at peripheral sympathetic nerve endings has been the subjects of investigation for over 25 years. The various metabolites are formed by sequential O-methylation deamination, and oxidation of the aldehyde or glycol derivatives. O-methylation to normetanephrine occurs after release of the catcholamine in an active form whereas norepinephrine which is metabolized in neuronal tissue is converted mainly to 3,4-dihydroxyphenylglycol (DHPG). This neutral metabolite readily diffuses into extraneural tissue where it is O-methylated to 3-methoxy-4-hydroxy-phenylglycol (MHPG). The glycol can be oxidized to form 3-methoxy-4-hydroxymandelic acid (VMA) which is also a major product of hepatic or renal metabolism of normetanephrine. In humans, VMA is the major urinary excretion product of the catecholamine, epinephrine and norepinephrine. MHPG produced in brain on peripheral tissues is conjugated or converted to VMA so that the total of urinary conjugated MHPG plus VMA reflects overall synthesis and metabolism of norepinephrine. Normetanephrine and metanephrine are formed primarily from activated catecholamines; the ratio of these amines to the deaminated compounds provides a useful index of symphato-adrenal medullary activity in disease states or after drug administration.