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PubMed2005

Tyrosine and tyramine increase endogenous ganglionic morphine and dopamine levels in vitro and in vivo: cyp2d6 and tyrosine hydroxylase modulation demonstrates a dopamine coupling.

BACKGROUND: The ability of animals to make morphine has been in question for the last 30 years. Studies have demonstrated that animals do contain morphine precursors and metabolites, as well as the ability to use some morphine precursors to make morphine. MATERIAL/METHODS: The present study uses excised ganglia from the marine invertebrate Mytilus edulis as well as whole animals. Morphine and dopamine levels were determined by high performance liquid chromatography coupled to electrochemical detection and radioimmunoassay. Tissues and whole animals were also exposed to morphine precursors and exposed to the CYP2D6 inhibitor quinidine and the tyrosine hydroxylase inhibitor alpha-methyl-para-tyrosine (AMPT). Additionally, via RT-PCR, a cDNA fragment of the CYP2D6 enzyme in the ganglia of M. edulis was identified. RESULTS: Pedal ganglia incubated with either tyramine or tyrosine, or whole animals receiving injections, exhibited a statistically significant concentration- and time-dependent increase in their endogenous morphine and dopamine levels (2.51 +/- 0.76 ng/g for tyrosine and 2.39 +/- 0.64 ng/g for tyramine compared to approximately 1.0 ng/g morphine wet weight). Incubation with quinidine and/or AMPT diminished ganglionic morphine and dopamine synthesis at various steps in the synthesis process. We also demonstrated that CYP2D6 mediates the tyramine to dopamine step in this process, as did tyrosine hydroxylase in the step from tyrosine to L-DOPA. Furthermore, via RT-PCR, we identified a cDNA fragment of the CYP2D6 enzyme in the ganglia, which exhibits 94% sequence identity with its human counterpart. Evidence that tyrosine and tyramine were, in part, being converted to dopamine then morphine, and that this process can be inhibited by altering either or both CYP2D6 or tyrosine hydroxylase, is also provided. CONCLUSIONS: It appears that animals have the ability to make morphine. This process also appears to be dynamic in that the inhibition of one pathway allows the other to continue with morphine synthesis. Moreover, dopamine and morphine synthesis were coupled.

Animals↗
PubMed1989

[Hypertensive crises with reversible inhibitors of monoamine oxidases? Results of tyramine interaction studies].

Healthy ambulatory subjects took 6 different MAO inhibitors (MAOIs) orally for 2 to 4 weeks. The new reversible MAO-A inhibitors brofaromine and moclobemide were compared with the irreversible MAOIs clorgyline, selegiline, phenelzine and tranylcypromine. Pressor responsiveness to oral tyramine was assessed before, during and after treatment. In unmedicated subjects, doses of tyramine to raise systolic blood pressure by at least 30 mmHg (PD30) ranged between 200 and 800 mg. During treatment with MAOIs, the PD30 decreased. The ratio of median effective doses (ED50) of tyramine (pre- vs post-treatment) was: selegiline 5, moclobemide 7, brofaromine 10, clorgyline 10, phenelzine 13 and tranylcypromine 55. Pressor responsiveness normalized within 8 days after stopping the reversible MAOIs and 30 days after tranylcypromine. The increased sensitivity after phenelzine persisted for longer than 8 weeks and after clorgyline for longer than 15 weeks. The results suggest that the two reversible MAO-A inhibitors moclobemide and brofaromine carry a much reduced liability to tyramine-related hypertensive reactions.

Administration, Oral↗
PubMed1989

Effect of thyroidectomy on cardiovascular responses to hypoxia and tyramine infusion in fetal sheep.

Fetal sheep were thyroidectomized at 80 days' gestation and reoperated at 118-122 days for insertion of vascular catheters. The effects of hypoxaemia and intravenous tyramine infusion on plasma catecholamine concentrations, blood pressure and heart rate were then determined in experiments at 125-135 days' gestation. Age matched intact fetuses were also studied. Thyroidectomy was associated with increased concentrations of noradrenaline, adrenaline and dopamine in some thoracic and abdominal organs, increased noradrenaline concentrations in the cerebellum, and decreased adrenaline concentrations in the hypothalamus, cervical spinal cord, and superior cervical and inferior mesenteric ganglia. Arterial pressure was significantly lower in the thyroidectomized fetuses (34.0 +/- 0.15 mmHg) than in intact fetuses (44.7 +/- 0.2 mmHg; p less than 0.001). In contrast, plasma noradrenaline concentrations were significantly higher in the thyroidectomized fetuses (2.04 +/- 0.25 ng/ml) compared to the intact fetuses (0.99 +/- 0.08 ng/ml; P less than 0.001). In the intact fetuses there was a significant increase in plasma noradrenaline concentration and blood pressure during hypoxaemia, and bradycardia at the onset of hypoxaemia. In contrast, in the thyroidectomized fetuses hypoxaemia did not cause significant change in plasma catecholamine concentrations, blood pressure or heart rate. Infusion of tyramine produced a 1.9-fold increase of plasma noradrenaline in thyroidectomized fetuses compared to a 9.2-fold increase in the intact fetuses (P less than 0.05). Tyramine infusion caused a similar proportional increase of blood pressure in both thyroidectomized and intact fetuses. Heart rate decreased during the tyramine-induced hypertension in the intact fetus, but increased in the thyroidectomized fetuses.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1984

In vivo cardiovascular responses to isoproterenol, dopamine and tyramine after prolonged infusion of isoproterenol.

Effects of prolonged in vivo infusion of isoproterenol on acute cardiovascular responses to isoproterenol, dopamine and tyramine were studied in pithed rats. Isoproterenol infusion resulted in a significant decrease in control values for maximum left ventricular dP/dt; heart rate and left ventricular systolic blood pressure were not altered. This treatment also depleted both atrial and ventricular stores of norepinephrine and caused cardiac hypertrophy. Isoproterenol infusion resulted in a desensitization of drug-induced cardiovascular responses. The acute in vivo effects of isoproterenol on maximum left ventricular dP/dt, heart rate and left ventricular systolic blood pressure responses to isoproterenol were severely attenuated. The ED50 for maximum left ventricular dP/dt was increased 36-fold and maximal responses were reduced by half; changes in heart rate occurred in a parallel fashion. By contrast, ED50 values for inotropic responses to tyramine and dopamine were increased 14- and 4-fold, respectively, whereas increases in heart rate were blunted. Tyramine and dopamine-mediated increases in heart rate were completely attenuated by desensitization; chronotropic effects were again evident after pretreatment with the selective alpha-1 blocker prazosin. In addition, prazosin blocked the inotropic responses to tyramine and dopamine after desensitization and this antagonism was only slightly enhanced by addition of propranolol (prazosin + propranolol); propranolol alone was ineffective. These results are consistent with the down-regulation of beta adrenoceptors after prolonged exposure to catecholamines and indicate that under such conditions the alpha-mediated cardiovascular responses may be unmasked. Compared to pure beta agonists, agents with a degree of alpha-1 activity might be superior inotropes in heart failure patients who characteristically present with depleted stores of myocardial norepinephrine and minimal beta adrenoceptor reserve.

Animals↗
PubMed1978

[Effect of tyramine on the cerebrovascular resistance and arterial pressure during the action of prostaglandins E].

A resistographic study of the cerebrovascular resistance (CVR) and of the arterial blood pressure showed prostaglandins (PG), type E, to inhibit the pressor action of tyramine on the cerebral vessels and the blood pressure. Indomethacin--an inhibitor of PG biosynthesis, retarded the tyramine tachyphylaxis and restored its pressor effect. Ipraside, the monoaminooxidase inhibitor, failed to influence the speed of tyramine tachyphylaxis development under conditions of indomethacin infusion, but increased the pressor effect of tyramine. It is supposed that inomethacin influence was based on the hypersensitivity of the vascular adrenoreceptors.

Animals↗
PubMed1984

Tyramine studies and the safety of MAOI drugs.

A major source of concern in using MAOIs is the risk of hypertensive crises, often called the "cheese effect" and thought to represent a drug-induced enhancement of the tyramine pressor effect. Several approaches to reduction of this risk are being explored, including use of inhibitors specific for the B vs. the A type of the enzyme, coadministration of tricyclic with MAOI, and development of reversible inhibitors which might be competitively displaced by tyramine. Such approaches require assessment of sensitivity to tyramine, usually given by the intravenous route. The oral tyramine pressor test, while cumbersome and in need of technical refinement, represents a significantly closer laboratory analogue to the clinical situation.

Administration, Oral↗
PubMed1995

Tumor-specific anti-epidermal growth factor receptor variant III monoclonal antibodies: use of the tyramine-cellobiose radioiodination method enhances cellular retention and uptake in tumor xenografts.

Amplification and rearrangement of the epidermal growth factor receptor (EGFR) gene are characteristics of many types of tumors. One class of EGFR mutations, EGFRvIII, is characterized by an in-frame deletion resulting in a truncated external domain of the receptor. EGFRvIII was first identified in a subset of gliomas and has since been found in some non-small cell lung carcinomas and breast carcinomas. mAbs specific for this variant form of EGFR but unreactive with the wild-type EGFR have been reported from our laboratory. This study further characterizes three of these antibodies. We determined, via radiolabeling techniques and immunofluorescence microscopy, that, after cell binding in vitro, the anti-EGFRvIII-specific mAbs internalize at 37 degrees C. Furthermore, subsequent to internalization, the antibodies were processed intracellularly, presumably by lysosomal degradation. We also examined the use of an alternative radiolabeling procedure that uses nonmetabolizable radio-iodinated tyramine cellobiose. Our results show that the tyramine cellobiose labeling method allows for greater tumor cell retention of radiolabel in vitro (76% for tyramine cellobiose and 27% for Iodo-Gen after 24 h). Paired-label biodistribution studies in athymic mice indicate that anti-EGFRvIII mAb L8A4 localizes specifically to EGFRvIII-expressing tumor xenografts with a maximum of 34.3 +/- 7.6% injected dose/g when labeled using tyramine cellobiose compared with a maximum of 14.9 +/- 4.3% injected dose/g using Iodo-Gen; similar results were obtained with mAb H10. These results suggest that the anti-EGFRvIII mAbs may serve as potential carriers for radioconjugate- and immunotoxin-based therapies for tumors expressing EGFRvIII.

Animals↗
PubMed1985

Retention and biliary excretion of poly-alpha, beta-[N(2-hydroxyethyl)-D,L-aspartamide] (PHEA) and its tyramine derivative (PHEA-Tyr) by isolated perfused rat liver. The role of molecular weight and chemical structure.

Isolated rat liver was perfused with fractions of fluorescent labelled poly-alpha,beta-[N(2-hydroxyethyl)-D,L-aspartamide] (PHEA), (Mw:8000, 51 400 and 70 000) and its tyramine derivative, PHEA-Tyr (19 mol% tyramine side chains; Mw:8000 and 35 000) under conditions approximating an "in vivo" situation. By an analysis of the recovered polymers it was shown, firstly that accumulation of polymers, which occurred most apparently in the Kupffer cells, was neither affected by the presence of tyramine side chains nor influenced by the molecular weight of polymers; secondly that the tyramine side chains slightly increased the biliary excretion of PHEA-Tyr, and thirdly with both types of polymers the excretion of high-molecular-weight fractions in the bile was strongly suppressed.

Animals↗
PubMed2004

Fluorinated phenylcyclopropylamines. 1. Synthesis and effect of fluorine substitution at the cyclopropane ring on inhibition of microbial tyramine oxidase.

Two series of diastereopure phenylcyclopropylamine analogues, 2-fluoro-2-phenylcyclopropylamines and 2-fluoro-2-phenylcyclopropylalkylamines, as well as 2-fluoro-1-phenylcyclopropylamines and 2-fluoro-1-phenylcyclopropylmethylamines, were synthesized in order to study the effects of fluorine substitution on monoamine oxidase inhibition. Inhibitory activity was assayed using commercially available microbial tyramine oxidase. Characterization of tyramine oxidase, carried out prior to the inhibition experiments, confirmed earlier suggestions that this enzyme is a semicarbazide-sensitive copper-containing monoamine oxidase. The most potent competitive inhibitor was trans-2-fluoro-2-phenylcyclopropylamine, which had an IC(50) value 10 times lower than that of the nonfluorinated compound, tranylcypromine. 2-Fluoro-1-phenylcyclopropylmethylamine was found to be a weak noncompetitive inhibitor of tyramine oxidase. The presence of a free amino group, directly bonded to the cyclopropane ring, and a fluorine atom in a relationship cis to the amino group were structural features that increased tyramine oxidase inhibition.

Binding Sites↗
PubMed2001

Functional expression of a locust tyramine receptor in murine erythroleukaemia cells.

The LCR/MEL system (Locus Control Region/Murine Erythroleukaemia cells) was employed to express and characterize the Locusta migratoria tyramine receptor (TyrLoc), an insect G protein-coupled receptor. Functional agonist-dependent responses were recorded in stable, tyramine receptor expressing cell clones (MEL-TyrLoc). Tyramine elicited a dose-dependent increase of cytosolic Ca2+-ions and an attenuation of forskolin-induced cyclic adenosine monophosphate (AMP) production. Octopamine was shown to be a weak agonist for both responses. In addition, yohimbine proved to be a potent tyramine receptor antagonist. This study reports the first application of the LCR/MEL expression system in functional assays for G protein-coupled receptors and therefore expands the capabilities of this system by exploiting the functionality of the signal transduction pathways.

Animals↗
PubMed1997

Purification, characterization and partial amino acid sequencing of hydroxycinnamoyl-CoA:tyramine N-(hydroxycinnamoyl)transferase from tobacco cell-suspension cultures.

We report the purification of hydroxycinnamoyl-CoA:tyramine N-(hydroxycinnamoyl)transferase (THT) to apparent homogeneity in 12% yield from tobacco (Nicotiana tabacum L. cv. Xanthi) cell-suspension cultures elicited with a commercial preparation of pronase. The purification procedure employs only four chromatography steps and takes advantage of the fact that the transferase binds tightly both to phenyl-Sepharose and to hydroxyapatite. The native enzyme has a pI of 5.2 and consists of two identical or very similar subunits of approximately 24 kDa. The purified enzyme can synthesise a wide range of amides due to its relatively low specificity for cinnamoyl-CoA derivatives and hydroxyphenethylamines, but its best substrates are tyramine and feruloyl-CoA. THT follows Michaelis-Menten kinetics in the presence of low concentrations of feruloyl-CoA but negative cooperativity occurs when this concentration increases above 2.5 microM, resulting in a marked decrease of the affinity for tyramine. Large deviations from Michaelis-Menten kinetics are also observed when 3-methoxytyramine is used as acyl acceptor. The activity of tobacco THT is not affected by the addition of CaCl2 or MgCl2 but its maximal velocity is increased up to twofold by addition of ethanol to the assay mixture. It is inhibited in vitro by L-tyrosine benzyl ester, which binds reversibly to the tyramine-binding site. Experiments performed using L-tyrosine benzyl ester and caffeoyl-CoA as inhibitors confirm that feruloyl-CoA is the first substrate to add to the transferase in an ordered bi-bi mechanism. Part of the amino acid sequence of the transferase, elucidated by microsequencing of tryptic peptides, is also described.

Acyltransferases↗
PubMed1990

Cloning and characterization of a Drosophila tyramine receptor.

Receptors for biogenic amines such as dopamine, serotonin and epinephrine belong to the family of receptors that interact with G proteins and share a putative seven transmembrane domain structure. Using a strategy based on nucleotide sequence homology between the corresponding genes, we have isolated Drosophila cDNA clones encoding a new member of the G protein-coupled receptor family. This protein exhibits highest homology to the human alpha 2 adrenergic receptors, the human 5HT1A receptor and a recently cloned Drosophila serotonin receptor. The corresponding mRNA is found predominantly in adult Drosophila heads. Membranes from mammalian cells expressing this receptor displayed high affinity binding sites for [3H]yohimbine, an alpha 2 adrenergic receptor antagonist (Kd = 4.45 x 10(-9) M). Tyramine was the most efficient of the putative Drosophila neurotransmitters at displacing [3H]yohimbine binding (EC50 = 1.25 x 10(-6) M). Furthermore tyramine induced an inhibition of adenylate cyclase activity in NIH 3T3 cells expressing this receptor. The Drosophila tyramine receptor that we have isolated might therefore be an invertebrate equivalent of the mammalian alpha 2 adrenergic receptors.

Amino Acid Sequence↗
PubMed1992

The modulatory effects of tryptamine and tyramine on the S9-mediated mutagenesis of IQ and MeIQ in Salmonella strain TA98.

The S9-mediated mutagenesis of IQ and MeIQ in Salmonella strain TA98 was modulated by introduction to the assay of tryptamine or tyramine. Both biogenic amines inhibited or enhanced the mutagenic response as a function of amine concentration, strain of rat used as the S9 source, and the IQ-type mutagen tested. Enhancement of IQ mutagenesis by tryptamine (10-80 microM) was observed in the presence of S9 preparations derived from Aroclor 1254-pretreated Fischer rats; the enhancing effect ceased at tryptamine concentrations > 160 microM. When Sprague-Dawley-S9 or Wistar-S9 were used for activation, the enhancement of IQ mutagenesis by tryptamine shifted to inhibition at tryptamine concentrations > 40 microM, with Sprague-Dawley-S9, and > 20 microM, with Wistar-S9. By contrast, MeIQ-mutagenesis was enhanced by tryptamine (10-160 microM), regardless of the rat strain used as S9 source. Tyramine was a weaker enhancer of MeIQ mutagenesis than was tryptamine and, unlike tryptamine, its inhibitory effects on IQ mutagenesis were observed only with Wistar-S9. Tryptamine (10-80 microM) inhibited cytochromes P450IA1 and P450IA2 activities, monitored by the O-deethylation of ethoxyresorufin and Glu-P-1 mutagenesis in TA98, respectively. These data suggest that the effects of biogenic amines on IQ and MeIQ bioactivation are complex. Furthermore, this study demonstrates that tryptamine and tyramine act both as enhancers (comutagens) and as inhibitors (antimutagens) of IQ and MeIQ mutagenesis, depending on the testing conditions.

Animals↗
PubMed1988

Enhanced pressor sensitivity to oral tyramine challenge following high dose selegiline treatment.

Blood pressure and heart rate responses to oral tyramine have been measured in healthy volunteers before and after administration of the selective monoamine oxidase B inhibitor selegiline at high dosage (30 mg/day). Treatment brought about a 2 to 4-fold increase in tyramine sensitivity and a concomitant small but significant reduction in plasma 4-hydroxy-3-methoxyphenylglycol concentration, pointing to the emergence of some degree of monoamine oxidase A inhibition. It is suggested that patients treated with selegiline 30 mg/day or more should be placed on a tyramine-free diet.

Adult↗
PubMed1991

The effect of angiotensin II on haemodynamic and plasma noradrenaline responses to tyramine infusion in man.

Six normal volunteers were studied on four separate occasions. On each occasion they received two concomitant infusions which were either placebo/placebo, placebo/tyramine, angiotensin II/placebo or angiotensin II/tyramine. Angiotensin II infusion was given at a constant rate of 2ng/kg/min whereas the tyramine infusion consisted of 10 min increments at 1.25, 2.5, 3.75, 5, 7.5 and 10 micrograms.kg-1.min-1. Tyramine infusion caused a dose dependent increase in systolic blood pressure with increases in diastolic blood pressure and plasma noradrenaline only at the highest doses. These changes were not affected by concomitant angiotensin infusion. We have therefore found no evidence to support the enhancement of haemodynamic or plasma noradrenaline responses to tyramine infusion by low dose infusion of angiotensin II in man.

Adolescent↗
PubMed1977

Effects of simple indoles, noradrenaline, nicotine, and tyramine on action potential and contractility of the isolated guinea-pig papillary muscle.

1. Simultaneous recordings of both the transmembrane action potential and the contractions were made in isolated electrically driven papillary muscles of the guinea pig in order to compare the effects of 6-methoxyindole (6-MOI), 3-methylindole (3-MI) and 5-methylindole (5-MI) with those of noradrenaline (1.2 - 10(-6) M), nicotine (2 - 10(-5) M), and tyramine (5.8 - 10(-6) M). 2. Noradrenaline, nicotine, tyramine and 6-MOI (5.4 - 10(-4) M) enhanced the contractility whilst 3-MI (3.8 and 7.8 - 10(-4) M) and 5-MI (1.9 and 3.8 - 10(-4) M) had only irregular effects. The active compounds shortened and time-to-peak tension and increased the rate of relaxation. 3. The duration of the action potential was prolonged by noradrenaline, nicotine, and tyramine, but shortened by 3-MI, 5-MI, and 6-MOI. 4. The results showed that the effect of drugs on the action potential are not necessarily linked to those on contractility.

Action Potentials↗
PubMed1977

Postnatal development of inotropic responses to nerve stimulation and tyramine in rat atria.

Inotropic responses were measured in isolated rat left atria using an isometric force transducer. In atria from adult rats tyramine administration or field stimulation of intramural cardiac nerves (in the presence of atropine) caused a positive inotropic response which was as great as that obtainable with exogenous noradrenaline. In contrast, atria from newborn animals showed very poor inotropic responses to nerve stimulation or tyramine although they already responded well to noradrenaline. The responses developed progressively with age, reaching adult levels at 3 to 4 weeks of age. It is concluded that the postnatal development of myocardial sympathetic nerves is correlated with a development of the positive inotropic response to sympathetic nerve stimulation or to tyramine.

Animals↗
PubMed1988

Effects of nutritional stress on brain tyramine concentration and dopamine turnover.

This is an investigation of the effect of nutritional stress at various ages on the levels of the p- and m-isomers of tyramine in the caudate nucleus of the rat. For comparison, the effects of nutritional stress on the concentration and turnover of dopamine were also studied. Nutritional stress induced in pre-weaning (3 weeks of age) or post-weaning (up to 9 weeks of age) rats resulted in a decrease in the concentration of p-tyramine and an increase in the concentration of m-tyramine in the caudate nucleus. Dopamine concentration or turnover in the caudate nucleus was not affected by pre-weaning undernutrition; in the olfactory tubercles, however, a significant decrease was observed in dopamine turnover, calculated from the decrease in homovanillic acid levels after monoamine oxidase inhibition. The results suggest the changes observed are dependent on the availability of the amino acid precursors p- and m-tyrosine and their competition towards aromatic-L-amino acid decarboxylase.

3,4-Dihydroxyphenylacetic Acid↗