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62

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

Synthesis and Metabolism:

Phenylalanine

DopamineSO

4

HVA

Tyrosine

DOPAC

3-MT

L-DOPA

Dopamine

PAH

TH

COMT

COMT

CYPD2

D H

SULT1A3

AADC

MAO-A/B

ALDH

MAO-A/B

ALDH

AADC

AADC

Tyrosine hydroxylase (TH) converts

the precursor amino acid tyrosine into

L-DOPA. Tyrosine hydroxylase is lo-

cated in dopamine and norepinephrine

neurons in various brain areas. In the pe-

riphery, TH is found in the adrenal me-

dulla and in sympathetic ganglia (nerve

clusters). Animal studies indicate that

selenium deficient diets increase the ac-

tivity of tyrosine hydroxylase two-fold.

Selenium deficiency also decreased the

expression of glutathione peroxidase

and glutathione reductase; decreased

expression of these enzymes may in-

crease intracellular oxidative stress. TH

enzyme function may be downregulated

by oxidative stress, nitrosative stress and

thiolation (reactions with sulfur amino

acids). Single nucleotide polymorphisms

(SNPs) in the genes coding for tyrosine

hydroxylase have been associated with

altered stress responses, blood pressure,

heart rate and norepinephrine secretion.

L-DOPA is converted to dopamine

by D

H; the enzyme requires copper

and ascorbate (Vitamin C) cofactors.

Dopamine is deaminated and dehydro-

genated to form (DOPAC) by mono-

amine oxidase A (MAOA) and aldehyde

dehydrogenase (ALDH). DOPAC is

then converted into homovanillic acid

(HVA) by catechol-O-methyltransferase

(COMT). Deficiency in COMT may el-

evate DOPAC levels and decrease 3-me-

thoxytyramine (3-MT) levels. COMT

requires S-adenosylmethionine (SAM)

and a magnesium cofactor. Pre-synaptic

uptake and metabolism of dopamine

give rise to 3,4-Dihydroxyphenylacetic

acid (DOPAC), a different metabolite.

Post-synaptic uptake and metabolism

produced both DOPAC and 3-MT.

Deficiency in either MAOA or

ALDH may result in DOPAC deficiency.

Enzyme deficiencies may be inherited

or acquired from nutritional deficiency

or toxicant exposure. Mutations or sin-

gle nucleotide polymorphisms (SNPs)

in MAOA genes have been associated

with aggression, behavior disorders, al-

coholism and attention deficit hyper-

activity disorder (ADHD). ALDH en-

zymes have multiple isoforms and three

different functional classes; they require

a magnesium cofactor. In vitro studies

indicate that mitochondrial ALDH2

contributes to neurotransmitter metab-

olism. Mutations that decrease ALDH2

are common in Asian populations and

may severely limit ALDH function.

Symptoms of ALDH deficiency include

erythema (flushing) of the skin after al-

cohol consumption, and may include

additional symptoms of nausea, head-

ache or physical discomfort. MAOA or

ALDH defects may decrease DOPAC

and increases 3-MT.

Plasma DOPAC levels are higher that

cerebrospinal fluid levels. Experimental

evidence indicates that most plasma

DOPAC originates in the peripheral

nervous system. Animal studies indi-

cate that plasma DOPAC may be par-

tially derived from metabolism of dopa-