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Functional Assessment of Urinary Neuro-biogenic Amines—A COMPREHENSIVE GUIDE 

69

dopamine by aromatic amino acid de-

carboxylase (AADC), using pyridoxal

phosphate (B6). Dopamine beta-hy-

droxylase (D

H) then converts dopa-

mine to norepinephrine. D

H requires

a copper cofactor, and abnormal cop-

per transport may decrease D

H ac-

tivity. Norepinephrine and other cate-

cholamines are sequestered in vesicles

by vesicular monoamine transporters

(VMAT) until released. The function

of VMAT may also influence norepi-

nephrine levels; plasma norepinephrine

levels are determined mainly by release

from intracellular vesicles. Reuptake oc-

curs through the norepinephrine trans-

porter (NET) in the cell membrane.

Sulfotransferase (SULT) enzymes are

not found in neurons. SULT1A3 catab-

olizes normetanephrine and its activity

may decrease in liver disease. SULT ac-

tivity has been down-regulated in vitro

by coffee compounds, green tea poly-

phenols, quercitin and resveratrol. SULT

enzymes also conjugate a variety of xe-

nobiotic chemicals that may be inhaled

or ingested during environmental expo-

sures. Some SULT enzymes are sensitive

to regulation by hormones, others con-

jugate hormones. Research continues in

this area.

Although norepinephrine and epi-

nephrine are primarily metabolized in

the same cellswhere they are synthesized,

catecholamine metabolism varies great-

ly between body organs. Sympathetic

nerves contain monoamine oxidase

(MAO) but not catechol-O-methyl-

transferase (COMT). Adrenal cells con-

tain both MAO and COMT enzymes.

COMT uses S-adenosyl-methionine

(SAM) and a magnesium cofactor; se-

lenium may improve MAO function.

Normetanephrine is a norepinephrine

metabolite of COMT, and is exclusively

an extra-neuronal metabolite. Contrary

to usual depictions of catecholamine

metabolism, vanillylmandelic acid

(VMA) is primarily produced by oxida-

tion of norepinephrine metabolite 3-me-

thoxy-4-hydroxyphenylglycol (MHPG),

and metabolized by alcohol and alde-

hyde dehydrogenases. The presence of

a beta-hydroxyl group on norepineph-

rine, epinephrine and their metabolites

favors reduction by aldehyde or aldose

reductases. Metabolites measured in the

mesenteric organs indicate that about

half of all norepinephrine is produced in

the gastrointestinal tract, pancreas, and

spleen. Most of the norepinephrine pro-

duced by mesenteric organs is removed

by the from portal vein blood by the liv-

er and converted to VMA for excretion.

Uptake of circulating catecholamines by

the liver and kidney, while important for

the clearance of catecholamines, con-

tributes less than 25% of the total me-

tabolism of catecholamines.

Receptors

Adrenergic receptors bind catechol-

amine neurotransmitters such as norepi-

nephrine and epinephrine. If signaled by

the CNS, preganglionic nerves using ace-

tylcholine neurotransmitters will stim-

ulate postganglionic nerves to secrete

norepinephrine into target receptor syn-

apses in cells and tissues. The binding of

norepinephrine to the receptors primar-

ily stimulates the sympathetic nervous

system. Norepinephrine concentrations

in the target receptor’s synapse is reg-

ulated by the CNS and pre-ganglionic

neurons.

Alpha adrenergic receptors affect

vasoconstriction and gastrointestinal

motility. There are multiple adrener-

gic receptor subtypes; each is encoded

separately in the DNA. Alpha recep-

tors stimulate the production of second

messenger molecule inositol 1,4,5-tris-