Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.14.16.2 (tyrosine hydroxylase)
 14,760 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The present paper describes the effect of beta-phenylethylamine and its metabolites phenylethanolamine, tyramine, acetyl-phenylethylamine and phenylacetaldehyde on the dopaminergic nigrostriatal system. The rotational behavioural response to the i.v. injection of these drugs was quantified in animals with a unilateral 6-hydroxydopamine lesion of the nigrostriatal dopamine system. Only beta-phenylethylamine and acetyl-phenylethylamine induced rotations ipsilateral to the side of the brain lesion. None of the compounds under study stimulated contralateral rotations. Acetyl-phenylethylamine was 90% less active than beta-phenylethylamine. After beta-phenylethylamine injection all animals (16/16) showed ipsilateral rotations. The dose-response curve showed that at doses as low as 1.75 mg/kg ipsilateral turns increase, with a dose-related rotational response between 1.75 mg/kg and 11.66 mg/kg, no differences being found at doses between 11.66 and 29.16 mg/kg. Rotations began a few seconds after beta-phenylethylamine injection. The highest response was found 30-60 s after the injection. The duration of the response was dose-related (4 min for the 3.5 mg/kg doses). The inhibition of dopamine-beta-hydroxylase activity with [1-3,5-difluorobenzyl)imidazole-2-thiol (SKF102698) did not modify the rotational response to beta-phenylethylamine. The inhibition of type B monoamine oxidase activity with l-deprenyl induced a slight increase in the ipsilateral rotational response to beta-phenylethylamine. The inhibition of tyrosine hydroxylase activity with alpha-methyl-p-tyrosine decreased the rotational response to beta-phenylethylamine. The dopamine receptor antagonist, haloperidol, completely blocked the ipsilateral rotational response to beta-phenylethylamine. The blocking of dopamine uptake into storage vesicles with reserpine increased the rotational action of beta-phenylethylamine. Taken together, the data suggest that, at low doses, beta-phenylethylamine stimulates the release of dopamine from the cytoplasmic pool and behaves as a dopamine receptor agonist with a very rapid and brief action.
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PMID:Action of beta-phenylethylamine and related amines on nigrostriatal dopamine neurotransmission. 866 50

Parkinson's disease (PD) is believed to be induced by the interaction of genetic predisposition and environmental factors, and a type of neurotoxin is proposed to be one of the environmental factors. We designed and synthesized a molecule, 1-benzyl-1,2,3,4-tetrahydroisoquinoline (1BnTIQ) as a possible PD-eliciting neurotoxin and evaluated its characteristics relevant to PD. 1BnTIQ is an endogenous amine in the brain and the 1BnTIQ content increases in the patients with PD. Repeated administration of 1BnTIQ induced PD-like symptoms in monkeys and mice. 1BnTIQ was biosynthesized from 2-phenylethylamine and phenylacetaldehyde, which is a metabolite of 2-phenylethylamine, and used in in vivo and in vitro studies. 1BnTIQ inhibited [3H] dopamine uptake in HEK293 cells which stably express dopamine transporter. 1BnTIQ also inhibited NADH-ubiquinone oxidoreductase (complex I) in the mitochondrial respiratory chain. Next, we assessed 1BnTIQ neurotoxicity in the organotypic coculture of the ventromedial portion of the mesencephalon and striatum. 1BnTIQ decreased the dopamine content in the mesencephalon in both dose- and time-dependent manners and it irreversibly reduced the dopamine content. Furthermore, it caused morphological changes in tyrosine hydroxylase-positive cells in the mesencephalon and reduced the number of cells. 1-(3',4'-Dihydroxybenzyl)-1,2,3,4-tetrahydroisoquinoline (3'4'DHBnTIQ) is also an endogenous parkinsonism-inducing 1BnTIQ derivative. In vivo and in vitro studies revealed that 3'4'DHBnTIQ was O-methylated by soluble catechol-O-methyltransferase (COMT). The result that COMT inhibitor suppressed 3'4'DHBnTIQ neurotoxicity suggests that 3'4'DHBnTIQ is metabolically activated by COMT to exert toxic effects.
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PMID:[Tetrahydroisoquinoline derivatives as possible Parkinson's disease-inducing substances]. 1244 Jan 54