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112

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

promote the release of norepinephrine

from nerve endings. Foodstuffs such as

hard cheeses and red wines contain large

amounts of tyramine. Normally, dietary

tyramine is metabolized in the gastroin-

testinal tract and liver before the amine

can enter the systemic circulation. If

monoamine oxidase A (MAO-A) is in-

hibited by medication or if enzyme

function is deficient, tyramine is able to

reach the sympathetic nerve terminals,

and paroxysmal hypertension and head-

ache may result from release of vesicular

norepinephrine.

Trace amines may be generated in

the gastrointestinal tract by protein-fer-

menting gut bacteria after a protein-rich

meal, and they may be found in a vari-

ety of foods as the result of food spoil-

age or deliberate fermentation. Dietary

trace amines are usually metabolized

quickly by MAO enzymes. Elevated

levels of trace amines may occur due to

phenylketonuria, ergot poisoning or the

use of monoamine oxidase inhibitors

(MAOIs). Elevated levels of the precur-

sor amino acid tyrosine may result in el-

evated levels of tyramine.

Synthesis and Metabolism:

Phenylalanine

DopamineSO

4

HVA

Tyrosine

Phenylethylamine

Tyramine

DOPAC

3-MT

L-DOPA

Dopamine

MAO-B

MAO-A/B

PAH

TH

COMT

COMT

CYPD2

D H

SULT1A3

AADC

MAO-A/B

ALDH

MAO-A/B

ALDH

AADC

AADC

Tyramine is the metabolite of the

aromatic amino acid tyrosine. It is syn-

thesized by aromatic L-amino acid de-

carboxylase (AADC), which is the

rate-limiting step for trace amine syn-

thesis.AADC is widely expressed within

the CNS and throughout the body, and

requires pyridoxal phosphate (vitamin

B6) as a cofactor. Trace amines may also

be synthesized through the metabolism

of secondary amines (molecules that

contain N-methyltyramine). Tyramine,

and other trace amines are found at low

(nanomolar) levels in the brain and the

peripheral nervous system; they repre-

sent less than 1% of the total volume

of biogenic amines in the central ner-

vous system (CNS). Secondary amines

may be converted to trace amines by

methyltransferase enzymes, which are

also widely expressed in the brain and

peripheral tissues. Methyltransferase

enzymes require S-adnosylmethionine

(SAM) as a cofactor. SAM must be

synthesized inside neurons behind the

blood brain barrier through an enzyme

pathway now commonly referred to as

the methylation cycle.

In vitro

and animal studies indicate

that the cytochrome P450 enzyme

CYP2D may, in the brain, convert tyra-

mine into dopamine. The contribution

of this pathway to the dopamine pool,

and its effects on neurotransmitter and

trace amine homeostasis, are still un-

der investigation. CYP2D expression

may be upregulated by nicotine, alco-

hol and some psycho-active drugs (such

as nefazodone and clozapine). CYP2D