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.
References:
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- Montoya A, Escobar R, Garcia-Polavieja MJ, et al. Changes of urine dihydroxyphenylglycol to norepinephrine ratio in children with attention-deficit hyperactivity disorder (ADHD) treated with atomoxetine. J Child Neurol. 2011;26(1):31-36.
- Hopkins SC, Sunkaraneni S, Skende E, et al. Pharmacokinetics and Exposure-Response Relationships of Dasotraline in the Treatment of Attention-Deficit/Hyperactivity Disorder in Adults. Clin Drug Invest. 2016;36(2):137-146.
- Garvey M, Hollon SD, DeRubeis RJ, Evans MD, Tuason V. Does 24-h urinary MHPG predict treatment response to antidepressants? I. A review. J Affect Dis. 1990;20(3):173-179.
- Perry G, Fitzsimmons B, Shapiro L, Irwin P. Clinical study of mianserin, imipramine and placebo in depression: blood level and MHPG correlations. Br J Clin Pharmacol. 1978;5(S1):35S-41S.
- Eisenhofer G, Kopin IJ, Goldstein DS. Catecholamine metabolism: a contemporary view with implications for physiology and medicine. Pharmacol Rev. 2004;56(3):331-349.
- Mardh G, Luehr CA, Vallee BL. Human class I alcohol dehydrogenases catalyze the oxidation of glycols in the metabolism of norepinephrine. Pro Nat Acad Sci USA. 1985;82(15):4979-4982.
- Freedman RR. Biochemical, metabolic, and vascular mechanisms in menopausal hot flashes. Fertility Sterility. 1998;70(2):332-337.
- Freedman RR. Pathophysiology and treatment of menopausal hot flashes. Paper presented at: Seminars in reproductive medicine2005.
- Gaweesh SS, Abdel-Gawad MMM, Nagaty AM, Ewies AAA. Folic acid supplementation may cure hot flushes in postmenopausal women: a prospective cohort study. Gynecol Endocrinol. 2010;26(9):658-662.
- Müller HU, Riemann D, Berger M, Müller W. The influence of total sleep deprivation on urinary excretion of catecholamine metabolites in major depression. Acta Psych Scand. 1993;88(1):16- 20.
- Baliga L, Rao A, Raja A, Rao SN. A study of urinary excretion of biogenic amine metabolites in epilepsy. Acta Neurol Scand. 1983;68(6):413-416.
- Garvey MJ, Tollefson GD, Orsulak PJ. Elevations of urinary MHPG in depressed patients with panic attacks. Psychiatry Res. 1987;20(3):183-187.
- Frankenhaeuser M, Lundberg U, Rauste von Wright M, von Wright J, Sedvall G. Urinary monoamine metabolites as indices of mental stress in healthy males and females. Pharmacol Biochem Behav. 1986;24(6):1521-1525.
- Lehnert H. Pheochromocytoma: Pathophysiology and Clinical Management. Vol 31: Karger Medical and Scientific Publishers; 2004.
- Seiden LS, Miller FE, Heffner TG. Neurotransmitters in Attention Deficit Disorder. Attention Deficit Disord Pod: Attention Deficit Disord Pod. 2013:223.
- Schildkraut JJ, Orsulak PJ, Schatzberg AF, et al. Toward a biochemical classification of depressive disorders. I. Differences in urinary excretion of MHPG and other catecholamine metabolites in clinically defined subtypes of depressions. Arch Gen Psychiatry. 1978;35(12):1427-1433.
- Gerner RH, Gwirtsman HE. Abnormalities of dexamethasone suppression test and urinary MHPG in anorexia nervosa. Am J Psych. 1981.
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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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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.
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3,4-Dihydroxyphenylpropionate, 3-Methyl-4-OH-phenylglycol, 5-Hydroxyindoleacetate, 8-Hydroxy-2-deoxyguanosine, a-Hydroxybutyrate, a-Hydroxyisobutyrate, a-Keto-b-Methylvalerate, a-Ketoadipate, a-Ketoglutarate, a-Ketoisocaproate, a-Ketoisovalerate, a-Ketophenylacetate, Adipate, b-Hydroxybutyrate, b-Hydroxyisovalerate, b-Hydroxypropionate, Benzoate, Cis-Aconitate, Citramalate, Citrate, Creatinine, D-Arabinitol, Formiminoglutamate, Glutarate, Glycerate, Glycolate, Hippurate, Homovanillate, Hydroxymethylglutarate, Indoleacetate, Isocitrate, Isovalerylglycine, Kynurenate, Kynurenate/Quinolinate, Lactate, m-Hydroxyphenylacetate, Malate, Methylmalonate, Orotate, Oxalate, p-Hydroxyphenylacetate, Phenylacetate, Pyroglutamate, Pyruvate, Quinolinate, Suberate, Succinate, Tartarate, Vanilmandelate, Xanthurenate
