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)

Previous studies indicating the importance of catecholamine metabolism in neuroblastoma were briefly reviewed. Metabolic pathways were presented showing how the major urinary metabolites 3-methoxy-4-hydroxymandelic acid (VMA) and 3-methoxy-4-hydroxy-phenylacetic acid (HVA) are formed from norepinephrine and from dopamine plus 3,4-dihydroxyphenylalanine (DOPA), respectively. For 289 neuroblastoma patients at the time of diagnosis, the urinary excretion of VMA was significantly elevated in 75%, and HVA was elevated in 80%. Periodic assay of these metabolites during the course of the disease revealed that the excretion trends were of prognostic value with 80-90% reliability. By contrast, when the excretion in only the initial urine specimens was considered, the survival rate was the same for patients with normal, and with significantly elevated, excretion. Review of the results of tracer studies aimed at elucidating the in vivo metabolic origins of the urinary metabolites suggested that a) in neuroblastoma, the catecholamines were largely inactivated by intracellular metabolism in the tumor cells; b) there was excess production and excretion of the norepinephrine precursors, DOPA and dopamine; and c) in the tumors of most neuroblastoma patients, the initial enzyme in catecholamine synthesis, tyrosine hydroxylase, had an activity comparable with that in normal adrenal glands. The importance of the metabolism of catecholamines in patients with neuroblastoma was stressed: a) The excretion of elevated levels of urinary catecholamine metabolites were useful in diagnosis and in following the course of the disease, and b) study of the catecholamine metabolism in these patients permitted examination of possible relationships between the activity of the enzymes involved in catecholamine synthesis and the malignancy of this tumor.
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PMID:Catecholamine metabolism in neuroblastoma. 1 Apr 50

Determinations of various catecholamines and their metabolites have been performed on 24-hr urine collecions obtained from a patient with torsion dystonia and compared to values obtained in a control population. This study was initiated following significant symptomatic worsening by the patient with supplemental ascorbic acid at a dosage of 2 g/day. Compared to base-line values, there resulted no significant alteration in urinary excretion of DOPA, dopamine, norepinephrine, epinephrine, or VMA for either the patient or a group of controls, receiving 1 g/day vitamin C. MHPG is the glycol metabolite of norepinephrine, and is produced both in central and systemic tissues, whereas VMA is not synthesized in brain. The MHPG excretion for the patient increased 150% with supplemental ascorbate, whereas the control individuals demonstrated a mean increase of 19.6%. It is possible that the symptomatic worsening by the patient and the increased excretion of MHPG in response to supplemental ascorbic acid are causally related. Ascorbic acid affects catecholamine biosynthesis at two metabolic loci; it is the necessary cofactor for dopamine-beta-hydroxylase and, by maintaining biopterin in reduced form, facilitates tyrosine hydroxylase holoenzyme activity. Thus, the vitamin may have effected increased central synthesis or turnover of norepinephrine, or both, with resultant clinical worsening.
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PMID:Effect of supplemental ascorbic acid in a case of torsion dystonia. 94 77

Young adult male CD-1 mice were treated orally twice weekly for three weeks with 0, 0.05, 0.15 or 0.65 mg/kg of aflatoxin B1 (AFB1) in corn oil. Two days after the last dose, the mice were killed by decapitation and the concentrations of the brain catecholamines, norepinephrine (NE), and dopamine (DA), and their metabolites, 3-methoxy-4-hydroxymandelic (VMA), homovanillic acid (HVA) and dihydroxyphenyl acetic acid (DOPAC) and the indoleamine serotonin (5-HT) and its metabolite, 5-hydroxyindoleacetic acid (5-HIAA) were determined by high pressure liquid chromatography in six discrete brain regions. Major effects of AFB1 were found in the concentrations of NE in most brain areas. Endogenous concentrations of DA were increased in the striatum and hypothalamus. The VMA level in the hypothalamus and striatum were decreased by the treatment. The activity of tyrosine hydroxylase, tryptophan hydroxylase, amino acid decarboxylase and monoamine oxidase (the enzymes important in synthetic and degradation pathways of biogenic amines) were investigated. Alterations in biogenic amine concentrations were often consistent with the changes observed in metabolizing enzymes. There was an increase noted in tryptophan hydroxylase activity. Activities of amino acid decarboxylase and monoamine oxidase were increased although the changes were not consistent in all regions or at all dose levels of AFB1. These results suggest that dietary exposure to AFB1 diets may cause alterations in various biogenic amine concentrations and related metabolizing enzymes.
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PMID:Alteration of biogenic amines in mouse brain regions by alkylating agents. I. Effects of aflatoxin B1 on brain monoamines concentrations and activities of metabolizing enzymes. 249 75

Two neurotransmitter-synthesizing enzymes, tyrosine hydroxylase (TH) and choline acetyltransferase (CAT), were assayed in neuroblastoma tissues from 24 children, in human neuroblastoma tissues serially transplanted in nude mice, and in human neuroblastoma cells in culture. Among tissues from 24 children, five showed an adrenergic pattern with significant TH activity alone, seven showed a cholinergic pattern with significant CAT activity alone, and the remaining 12 specimens showed a "both-active" pattern with both TH and CAT activity. Enzymatic activities were maintained through many serial passages in vitro and in nude mice. All four specimens from children under one year of age exhibited the adrenergic pattern. In general, enzymatic activity was not correlated with degree of differentiation histologically. Among four cases of paravertebral dumb-bell type in this series, two were cholinergic, one was adrenergic, and the last was both-active. These results suggest that dumb-bell type tumors may arise from either sympathetic ganglia or dorsal root ganglia. This study supports the concept that neuroblastomas are a composite of adrenergic and cholinergic cells. Significant changes in the relative proportions of these two cell types were observed with time, and after extensive therapy. Different metastatic sites often exhibited important differences in enzymatic activity. These results help to account for clinical discrepancies between urinary VMA levels and tumor growth. Assays for TH and CAT can be useful for confirming a diagnosis of neuroblastoma, and have important potential for helping to clarify the natural history of neuroblastoma.
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PMID:Tyrosine hydroxylase and choline acetyltransferase activity in human neuroblastoma. Correlations with clinical features. 613 77

Among the enzymes involved in the system for catecholamine biosynthesis, GTP cyclohydrolase I (GCH) contributes to the system as the first and rate-limiting enzyme for the de novo biosynthesis of tetrahydrobiopterin (BH4), which is the cofactor for tyrosine hydroxylase (TH). Therefore, we investigated whether the endotoxemia caused by an intraperitoneal (i.p.) injection of lipopolysaccharide (LPS) can modulate BH4 production in the norepinephrine nuclei, i.e. the locus ceruleus (LC; A6) and central caudal pons (A5), in C3H/HeN mice and whether such a change in BH4, if any, can result in the modification of norepinephrine production in these nuclei. After a 5-microg i.p. injection of LPS, the protein expression of GCH and TH in both nuclei was examined by immunohistochemistry. The staining intensity of GCH-positive cells increased at 6 h, whereas no significant change in the staining intensity of TH-positive cells was detected. Next, we measured the contents of BH4, norepinephrine, and its metabolites 4-hydroxy-3-methoxyphenylglycol (MHPG) and DL-4-hydroxy-3-methoxymandelic acid (VMA) in these nuclei after LPS i.p. injection. The BH4 content increased to a statistically significant level at 2 and 4 h after the injection. The contents of MHPG and VMA also showed a time-course similar to that of BH4. These data can be rationalized to indicate that an increased supply of BH4 in the LC increased TH activity and resulted in an increase in norepinephrine production rate at the site. This is the first report that sheds light on BH4 as a molecule that intervenes during endotoxemia to increase norepinephrine production rate in the LC.
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PMID:Expression of GTP cyclohydrolase I in murine locus ceruleus is enhanced by peripheral administration of lipopolysaccharide. 1116 86