Metabolism of endogenous catecholamines
Steps of catecholamine biosynthesis and enzymes involved are indicated in the table attached: phenylalanine is converted successively into tyrosine, dihydrophenylalanine (DOPA), dopamine, norepinephrine (noradrenaline) and epinephrine(adrenaline).
Catecholamine biosynthesis is regulated at the tyrosine hydroxylase step. Tyrosine hydroxylase, present in the cytoplasm, is the rate- limiting enzyme. Stimulation of adrenergic nerves increases tyrosine hydroxylase activity.
This enzyme requires the presence of tetrahydrobiopterine, itself regenerated by reduced nicotinamide adenine dinucleotide.
The steps of the synthesis of catecholamines proceed in different cellular structures: tyrosine penetrates into the cytoplasm of neurons where it is converted to DOPA then to dopamine which penetrates into storage vesicles where it can be converted into noradrenaline by dopamine-ß-hydroxylase.
Storage vesicles are smaller and denser than mitochondria and contain adenosine triphosphate or ATP, catecholamines (4 catecholamine molecules for 1 molecule of ATP), calcium and magnesium, as well as proteins called chromogranines. Monoamine oxidase is present in adrenergic terminations, but not in storage vesicles.
- Adrenal medulla is the organ richest in catecholamines. It contains much more adrenaline than noradrenaline.
- Organs with sympathetic innervation, such as heart and vessels, contain noradrenaline. They can, moreover, take up circulating catecholamines like adrenaline from plasma. The sympathetic postsynaptic fibers synthesize norepinephrine, but not adrenaline.
- Brain, rich in noradrenaline and dopamine (extrapyramidal system), contains little adrenaline.
Like other transmitters, endogenous catecholamines are active only after their release. Under the effect of the nervous impulse, sympathetic terminations release norepinephrine, adrenal medulla releases adrenaline and norepinephrine.. This release is carried out by exocytosis, storage vesicles coming to break in contact with the cellular membrane.
As the adrenergic receptors are in contact with sympathetic terminations, norepinephrine released acts primarily on the organs where it is released and passes only secondarily in general circulation, whereas adrenaline and norepinephrine released by the adrenal medulla pass directly into blood.
The plasma concentration of a compound results from its release into plasma, its uptake by tissues and its catabolism. In people lying at rest, plasma concentrations of dopamine, epinephrine and noradrenaline are low (less than 1 microgram per liter), but they can rise under physiological (adaptation) or pathological conditions. For example, when one goes from the supine to the standing position, noradrenaline concentration increases two fold. In patients with pheochromocytoma plasma catecholamines can rise transiently and reach high levels .
Catecholamines are quickly inactivated, metabolized by the enzymes catechol-oxymethyltransferase (COMT) and monoamine oxidase (MAO), and by neuronal and extraneuronal reuptakes. Their physiological effects are thus fugacious
COMT, primarily extraneuronal, catalyzes methylation of one of the two oxygen atoms of the nucleus catechol. In biological media, methylation is carried out preferentially in position 3 or méta. Monophenol derivatives are not methylated, which would explain, at least partly, their longer duration of action.
The products obtained from catecholamine catabolism induced by COMT are metanephrine, normetanephrine and the 3-methoxy-4-hydroxy-phenyl-ethylamine or 3-methoxy-dopamine whose urinary elimination can increase in patients with pheochromocytoma.
COMT inhibitors reinforce and prolong the effects of catecholamines.
MAO indicates an enzyme group present inside the neurons, but also in plasma, which catalyzes the oxydative deamination of monoamines: adrenaline, noradrenaline, dopamine, serotonin. It catalyzes the transformation of an amine into an aldehyde according to the following reaction
The aldehyde R-CHO is then oxidized into acid by aldehyde oxidase, which leads to 3-4-dihydroxy-mandelic acid resulting from adrenaline and noradrenaline, and homoprotocatechic acid resulting from dopamine. The aldehyde can also be converted to alcohol. Hydrogen peroxide is destroyed by catalase and peroxidase.
Inhibitors of monoamine oxidase (MAOI) inhibit this reaction and the content of monoamines in tissues rises. MAO inhibitors are used as antiparkinsonians and antidepressants.
Combined action of these two enzymatic processes
Methylation, preceding deamination or conversely, lead to vanylmandelic acid (VMA), homovanillic acid (HVA), but also to alcohols: methoxy-hydroxy-phenyl-glycol (MHPG) and methoxy-hydroxy-phenyl-ethanol (MHPE).
Catecholamines and their metabolites can be conjugated by sulfoconjugaison and glycuroconjugaison.
Exploration of catecholamine metabolism disorders, in particular for the diagnosis of pheochromocytoma, involves the determination of catecholamines, metanephrines in plasma and urine and VMA and HVA in urine.
Catecholamines released by adrenergic terminations are mainly reuptaken in the adrenergic terminations themselves,( intraneuronal reuptake or uptake 1) – and to a lesser extent by other tissues –( extraneuronal uptake or uptake 2).
Intraneuronal reuptake is ensured by carriers, sodium, chloride-dependant, specific either to noradrenaline or dopamine. The activity of these carriers is controlled in a complex way and can be inhibited by numerous drugs: several antidepressants, cocaine, amphetamine. The inhibition of the reuptake of a transmitter increases its concentration in the synaptic cleft.
Extraneuronal uptake exists in certain tissues particularly when released or administered catecholamine concentrations are very high. It is inhibited by normetanephrine and metanephrine. Its physiological role does not seem very important.
Catabolism of catecholamines