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80

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

Synthesis and metabolism:

NMet-SO

4

MHPG-SO

4

VMA

Met-SO

4

MHPG-SO

4

VMA

Normetanephrine

Metanephrine

DPHG

Norepinephrine

Epinephrine

SULT1A3

SULT1A3

MAO-A+AR

COMT

SULT1A3

ADH

COMT

COMT

PNMT

D H

MAO-A

MAO-A

AR

AR

Norepinephrine is converted to

epinephrine by phenylethanolamine

N-methyltransferase (PNMT). PNMT

requires an S-adenosyl methionine

(SAM) cofactor. Animal studies indicate

that PNMT activity may be upregulat-

ed by exercise, high cortisol levels (such

corticosteroid medications) or stress.

Epinephrine is stored in vesicles until it

is released into the circulation.

Metanephrine is produced out-

side of neurons (extra-neuronally).

Adrenomedullary chromaffin cells pos-

sess monoamine oxidase A (MAO-A)

and catechol-O-methyl transferase

(COMT). Approximately 90% of epi-

nephrine is metabolized before the

neurotransmitter is released. COMT

requires a magnesium cofactor and

S-adenosylmethionine. COMT is not

found in sympathetic nerves, but mono-

amine oxidase A (MAO-A) is. Contrary

to usual depictions of catecholamine

metabolism, vanillylmandelic acid

(VMA) is primarily produced by the

oxidation of the epinephrine metabo-

lite 3-methoxy-4-hydroxyphenylglycol

(MHPG), and is metabolized by alco-

hol and aldehyde dehydrogenases. The

presence of a beta-hydroxyl group on

epinephrine, norepinephrine and their

metabolites favors reduction by alde-

hyde or aldose reductases. Uptake of

circulating catecholamines by the liv-

er and kidney, while important for the

clearance of catacholamines, contributes

less than 25% of the total metabolism of

catecholamines.

Evidence indicates that sulfate-con-

jugated normetanephrine is instead

formed primarily in gastrointestinal tis-

sue. Sulfotransferase (SULT) enzymes

are not found in neurons. SULT activi-

ty has been down-regulated

in vitro

by

coffee compounds, green tea polyphe-

nols, quercitin and resveratrol. SULT

enzymes also conjugate a variety of xe-

nobiotic chemicals that may be inhaled

or ingested during environmental ex-

posures. Some SULT enzymes are sen-

sitive to regulation by hormones, others

conjugate hormones. SULT1A3 con-

verts epinephrine to metanephrine and

its activity may decrease in liver disease,

elevating levels of metanephrine and

normetanephrine.

In urinary assays, free metanephrines

represent a small proportion (<3%) of

the total measured normetanephrines.

Doctor’s Data measures total metaneph-

rines, which is the medical convention.

Consider:

Copper status

( RBC Elements )

Magnesium status

( RBC Elements

)

Status of neurotransmitter precursor

Phenylalanine

( Amino Acids )