3-Methyl-4-OH-Phenylglycol (MHPG) is a byproduct of the central nervous system’s norepinephrine (NE) metabolism. MHPG metabolizes to vanilmandelic acid (VMA) in the liver using the enzymes alcohol dehydrogenase and aldehyde dehydrogenase. Urinary MHPG was originally thought to represent CNS sympathetic output, but is now known to be principally derived from peripheral neuronal NE metabolism.
MHPG has been widely studied as a marker to predict response to medications used in mood disorders or as a biomarker to monitor pharmacotherapies.
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Since catecholamines are made from dopamine, low levels of the MHPG metabolite can result from low levels of dopamine, dopamine amino acid precursors, nutrient enzymatic cofactor deficiencies in dopamine metabolism, and overall methylation defects. Low levels of MHPG have been correlated to mood and behavioral disorders, anorexia, and ADHD.
The role of hepatic alcohol and aldehyde dehydrogenase explains the clinical observations that ethanol consumption decreases the excretion of VMA, while increasing MHPG.
Because norepinephrine is involved in the pathophysiology of hot flashes in postmenopausal women, MHPG levels have been studied in this patient population.
Interestingly, folic acid was found to interact with receptors causing subjective improvement in symptoms.
Sleep deprivation can act as a stimulus to the peripheral sympathetic nervous system, which can influence central nervous noradrenergic neurotransmitter levels and elevate MHPG.
As a central nervous system metabolite, levels can correlate with central catecholaminergic disturbances, as in anxiety and seizures.
Elevated MHPG levels have also been associated with the stress response.
Pheochromocytomas are rare, mostly benign tumors of the adrenal medulla which can secrete catecholamines causing a wide array of sympathetic symptoms. These tumors contain MAO and COMT. They can therefore produce MHPG. However, because peripheral sympathetic nerves can also contribute to high MHPG, using MHPG for diagnosis of pheochromocytoma limited. VMA is also not very sensitive for diagnosis of pheochromocytoma because it can be made in the liver from MHPG. Although neither organic acid is diagnostic of pheochromocytoma, it is possible to see elevations of these analytes in the disease.
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