Catecholamine Biosynthesis And Catabolism

Catecholamines are molecules with a catechol nucleus (benzene with two hydroxyl side groups) plus a side chain with an amine.1 Catecholamines include dopamine, epinephrine, and norepinephrine.

Sympathetic nerves (paraganglia) and the adrenal medulla belong to a family of secretory cells characterized by amine and amine precursor uptake and decarboxylation (APUD). Sympathetic nerves and adrenal medullary cells actively take up tyro-sine. Intracytoplasmic tyrosine is then converted to L-dihydroxyphenylalanine (dopa) by the enzyme tyrosine hydroxylase. Dopa is then changed to dopamine (L-dihydroxyphenylethylamine) by dopa decarboxylase. Dopamine enters granulated vesicles, where it is hydroxylated to norepinephrine by the enzyme dopamine P-hydroxylase. Norepinephrine is stored in the vesicle. The granulated storage vesicle migrates to the cell surface and secretes its contents via exocytosis. After secretion, most norep-inephrine is avidly recycled back into the nerve via a reuptake mechanism. Normally, most circulating norepinephrine originates from nonsecretory diffusion out of nonadrenal sympathetic nerve cells.

Norepinephrine in storage vesicles can diffuse into the cytoplasm. In certain cells (particularly the adrenal medulla), norepinephrine is converted to epinephrine in the cytoplasm, catalyzed by 4-phenylethanolamine-N-methyltransferase (PNMT). (Once formed, epinephrine may then return to the vesicle, diffuse from the cell, or undergo catabo-lism.) The expression of PNMT is enhanced by cortisol, which is present in high concentrations in areas of the adrenal medulla, owing to venous blood flow from the adjacent adrenal cortex. This accounts for the fact that, in the normal human adrenal medulla, about 80% of the catecholamine content is epinephrine, whereas only 20% is norepinephrine. Serum epinephrine concentrations fall dramatically after resection of both normal adrenals, whereas norepi-nephrine concentrations do not decline.1

Catecholamines are metabolized quickly to inactive compounds (the metanephrines, VMA, conjugated catecholamines). This occurs as follows: excess intracellular norepinephrine is inactivated primarily by intramitochondrial deamination by monoamine oxidase (MAO) and aldehyde dehydro-genase to an aldehyde that is then oxidized to 3,4-dihydroxymandelic acid; the latter is eventually converted via catechol O-methyltransferase (COMT) to VMA. Circulating norepinephrine is metabolized largely to normetanephrine by COMT, with the methyl donor being ¿-adenosylmethionine. COMT is an enzyme found in most tissues, especially blood cells, liver, kidney, and vascular smooth muscle. Epi-nephrine is similarly catabolized to metanephrine, which is then partly converted to VMA.

In normal individuals, the urine catecholamines/ metabolites are approximately 50% metanephrines,

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