m-Tyramine

Discovery and inhibition of an interspecies gut bacterial pathway for Levodopa metabolism

The human gut microbiota metabolizes the Parkinson's disease medication Levodopa (l-dopa), potentially reducing drug availability and causing side effects. However, the organisms, genes, and enzymes responsible for this activity in patients and their susceptibility to inhibition by host-targeted drugs are unknown. Here, we describe an interspecies pathway for gut bacterial l-dopa metabolism. Conversion of l-dopa to dopamine by a pyridoxal phosphate-dependent tyrosine decarboxylase from Enterococcus faecalis is followed by transformation of dopamine to m-tyramine by a molybdenum-dependent dehydroxylase from Eggerthella lenta These enzymes predict drug metabolism in complex human gut microbiotas. Although a drug that targets host aromatic amino acid decarboxylase does not prevent gut microbial l-dopa decarboxylation, we identified a compound that inhibits this activity in Parkinson's patient microbiotas and increases l-dopa bioavailability in mice.

The biosynthesis of p-tyramine, m-tyramine, and beta-phenylethylamine by rat striatal slices

Slices of striatal tissue obtained from saline-injected rats were incubated with 3H-phenylalanine in the presence of pargyline. This resulted in the formation of 3H-m-tyramine, 3H-p-tyramine, and 3H-phenylethylamine. Pretreatment of the rats with alpha-methyl-p-tyrosine reduced the formation of 3H-m-tyramine and 3H-p-tyramine, but enhanced the formation of 3H-phenylethylamine. After incubation of striatal tissue obtained from saline-injected rats with 3H-ptyrosine, only 3H-p-tyramine was produced. In this case, alpha-methyl-p-tyrosine pretreatment enhanced 3H-p-tyramine formation. Striatal slices incubated with 3H-m-tyramine or 3H-p-tyramine did not yield any significant quantity of 3H-phenylethylamine; nor was 14C-phenylethylamine converted to 14C-m-tyramine or 14C-p-tyramine. Pretreatment of the rats with the monoamine oxidase inhibitor pargyline did not appreciably affect these findings. After incubation with 3H-dopamine very small quantities of 3H-m-tyramine and 3H-p-tyramine were formed, the ratio between them being 7:1. It is concluded that the major biosynthetic route for m-tyramine formation in the rat striatum is by hydroxylation of phenylalanine, probably by tyrosine hydroxylase to m-tyrosine, followed by decarboxylation, probably by L-aromatic amino acid decarboxylase, to m-tyramine. para-Tyramine is formed by decarboxylation of p-tyrosine, and phenylethylamine similarly by decarboxylation of phenylalanine.

The role of catecholamines, 5-hydroxytryptamine and m-tyramine in the behavioural effects of m-tyrosine in the rat

The behavioural and neurochemical effects of m-tyrosine and a monoamine oxidase inhibitor in the rat are described. Systemic injections of m-tyrosine (50-150 mg/kg) 30 min after the administration of pargyline (75 mg/kg) produced intense behavioural stimulation which was not evident after injection of either compound alone. The behavioural syndrome induced consisted of forepaw padding, headweaving, backward walking, splayed hindlimbs, wet dog shakes, hyperactivity and hyperreactivity. m-Tyrosine alone or in combination with pargyline caused a significant increase in brain m-tyramine levels and a significant depletion of catecholamines. 5-Hydroxytryptamine (5-HT) levels, however, were unaffected by the administration of m-tyrosine at most of the times studied. The increase in levels of m-tyramine produced by m-tyrosine plus pargyline was 10 times greater than that produced by m-tyrosine alone, whereas the depletion in levels of the more abundant amines was not potentiated by pargyline pretreatment. The biochemical results suggest that an increased formation of m-tyramine may have been responsible for the observed behavioural stimulation and that a threshold level of m-tyramine in the brain appears to be necessary to produce an overt behavioural effect. The behavioural components observed indicate that m-tyramine could act by releasing newly synthesized catecholamines or 5-HT. Alternatively, m-tyrosine may function as a direct agonist at 5-HT or dopamine receptors, although an action on a specific tyraminergic receptor cannot be ruled out at present.

Electrochemical sensor for selective tyramine determination, amplified by a molecularly imprinted polymer film

A molecularly imprinted polymer (MIP) film based electrochemical sensor for selective determination of tyramine was devised, fabricated, and tested. Tyramine is generated in smoked and fermented food products. Therefore, it may serve as a marker of the rottenness of these products. Importantly, intake of large amounts of tyramine by patients treated with monoamine oxidase (MAO) inhibitors may lead to a "cheese effect", namely, a dangerous hypertensive crisis. The limit of detection at S/N = 3 of the chemosensor, in both differential pulse voltammetry (DPV) and electrochemical impedance spectroscopy (EIS) determinations, with the use of the Fe(CN)₆^4-/Fe(CN)₆^3- redox probe, was 159 and 168 ?M tyramine, respectively. The linear dynamic concentration range was 290 ?M to 2.64 mM tyramine. The chemosensor was highly selective with respect to the glucose, urea, and creatinine interferences. Its DPV determined apparent imprinting factor was 5.6. Moreover, the mechanism of the "gate effect" in the operation of the polymer film-coated electrodes was unraveled.

The effects of (+)-amphetamine, alpha-methyltyrosine, and alpha-methylphenylalanine on the concentrations of m-tyramine and alpha-methyl-m-tyramine in rat striatum

The concentration in rat striatum of the meta and para isomers of tyramine and alpha-methyltyramine, after the administration of (+)-amphetamine, alpha-methyl-p-tyrosine (AMPT) and alpha-methylphenylalanine (AMPA) has been determined using chemical ionization gas chromatography mass spectrometry (c.i.g.c.m.s.). Twenty hours after the last of 7 daily injections of (+)-amphetamine (5 mg kg-1 i.p.) the concentration of alpha-methyl-p-tyramine in striatal tissue increased twofold compared to the concentration 20 h after a single injection. In contrast the concentration of alpha-methyl-m-tyramine did not change. alpha-Methyl-m-tyramine and alpha-methyldopamine were found in the striatum at concentrations of 42 ng g-1 and 13.5 ng g-1 respectively after treatment of rats 20 h before with AMPA (100 mg kg-1 i.p.). After treatment with AMPT (100 mg kg-1, 20 h before decapitation) only the para isomer of alpha-methyltyramine could be detected (13.7 ng g-1) although the striatal concentration of alpha-methyldopamine was 274 ng g-1, a level 20 times greater than that observed after AMPA treatment. The combined administration of both AMPT and AMPA (100 mg kg-1 each, 20 h) resulted in a reduction of the striatal concentration of alpha-methyl-m-tyramine but not alpha-methyl-p-tyramine. These data suggest that alpha-methyl-m-tyramine in rat striatum is formed by the enzyme tyrosine hydroxylase on substrate AMPA, rather than by ring dehydroxylation of alpha-methyldopa and alpha-methyldopamine. Significant reductions in the striatal concentrations of m-tyramine 2 h after the administration of AMPT, suggest that tyrosine hydroxylase is involved similarly in the production of m-tyramine.