Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0031511 (pheochromocytoma)
 14,622 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Pheochromocytoma tyrosine hydroxylase was reported to have unusual catalytic properties, which might be unique to the tumor enzyme (Dix, T. A., Kuhn, D. M., and Benkovic, S. J. (1987) Biochemistry 24, 3354-3361). Two such properties, namely the apparent inability to hydroxylate phenylalanine and an unprecedented reactivity with hydrogen peroxide were investigated further in the present study. Tyrosine hydroxylase was purified to apparent homogeneity from cultured pheochromocytoma PC12 cells. The purified tumor enzyme was entirely dependent on tetrahydrobiopterin (BH4) for the hydroxylation of tyrosine to 3,4-dihydroxyphenylalanine and hydrogen peroxide could not substitute for the natural cofactor. Indeed, in the presence of BH4, increasing concentrations of hydrogen peroxide completely inhibited enzyme activity. The PC12 hydroxylase exhibited typical kinetics of tyrosine hydroxylation exhibited typical kinetics of tyrosine hydroxylation, both as a function of tyrosine (S0.5 Tyr = 15 microM) and BH4 (apparent Km BH4 = 210 microM). In addition, the enzyme catalyzed the hydroxylation of substantial amounts of phenylalanine to tyrosine and 3,4-dihydroxyphenylalanine (apparent Km Phe = 100 microM). Phenylalanine did not inhibit the enzyme in the concentrations tested, whereas tyrosine showed typical substrate inhibition at concentrations greater than or equal to 50 microM. At higher substrate concentrations, the rate of phenylalanine hydroxylation was equal to or exceeded that of tyrosine. Essentially identical results were obtained with purified tyrosine hydroxylase from pheochromocytoma PC18 cells. The data suggest that the tumor enzyme has the same substrate specificity and sensitivity to hydrogen peroxide as tyrosine hydroxylase from other tissues.
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PMID:The hydroxylation of phenylalanine and tyrosine by tyrosine hydroxylase from cultured pheochromocytoma cells. 167 41

Neuronal differentiation is influenced by extracellular factors; however, only a few such factors have been identified for central neurons. To address this issue, we have screened media conditioned (CM) by several glial cell lines for neurotrophic effects on dopaminergic neurons in dissociated cell cultures of the E14.5 rat mesencephalon grown in serum-free conditions. To establish culture conditions under which dopaminergic cell survival depends on the exogenous support from neurotrophic factors, cell suspensions were seeded at varying densities and the number of tyrosine hydroxylase-immunoreactive (TH-IR) neurons was determined. This number was maximal at plating densities greater than 175,000 cells/cm2 and was 10-fold lower at the plating density of 80,000 cells/cm2. Cell density had only a minimal effect on [3H]dopamine uptake per TH-IR neuron. Treatment of cultures plated at 80,000 cells/cm2 with CM derived from the glial cell line, B49, the neural retina glial cell line, R33, and the Schwannoma cell line JS1, increased the number of surviving TH-IR neurons 160-330%. These effects were dose dependent and heat sensitive. All CM stimulated neurite elongation of TH-IR neurons, while only the B49-CM increased [3H]dopamine uptake. The neurotrophic effects of these media were not confined to dopaminergic neurons but increased overall neuronal density in culture by 50-100%. Moreover, all three CM were mitogenic for mesencephalic glia as demonstrated by glial fibrillary acidic protein (GFAP)-immunocytochemistry in combination with [3H]thymidine-autoradiography. By contrast, medium conditioned by the pheochromocytoma cell line, PC12, did not increase the number of astrocytes or promote the survival of dopaminergic neurons. Inhibition of glial proliferation reduced the neurotrophic effects of the B49-, R33-, and JS1-CM by 40-80%. These observations suggest that the glial cell lines B49, R33, and JS1 secrete factors that promote the survival of dopaminergic neurons and induce proliferation of glial precursors. The partial decrease of the survival-promoting effects of these CM on dopaminergic neurons in glial-free mesencephalic cultures further suggests that the observed neurotrophic effects result from the combined action of cell line-derived substances directly on neurons and indirectly via effects on mesencephalic astrocytes or astrocyte precursors.
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PMID:Conditioned media derived from glial cell lines promote survival and differentiation of dopaminergic neurons in vitro: role of mesencephalic glia. 168 85

Membrane depolarization is an important and common manipulation used to study the result of enhanced neuronal activity on adaptive changes, including alterations in gene expression. In this study, the effect of elevated KCl, under isotonic and hypertonic conditions, on the changes in mRNA levels of the catecholamine biosynthetic enzymes, tyrosine hydroxylase (TH) and dopamine beta-hydroxylase (DBH) was compared. Treatment of PC12 pheochromocytoma cells for several hours with 50 mM KCl, under conditions where osmolarity was maintained, induced TH mRNA levels several fold, without changing DBH mRNA levels (Kilbourne and Sabban, 1990). In contrast, 50 mM KCl added to culture media without adjusting the osmolarity did not alter TH mRNA levels for up to 24 h. Longer continuous exposure to this hypertonic depolarization condition reduced TH mRNA levels to about 10% of control levels. DBH mRNA levels also declined when PC12 cells were treated from 12 h to 5 days with hypertonic 50 mM KCl. The effect appeared to be specific, since actin mRNA levels were elevated about 2-fold with these same hypertonic treatments. As a control for osmotic changes, 50 mM NaCl was used and did not alter TH or DBH mRNA levels. Viability of the cells was maintained and total protein synthesis was reduced somewhat after 12 h of exposure to hypertonic 50 mM KCl, and remained relatively constant for as long as 4 days. Thus, there appears to be an interaction between osmolarity and elevated KCl since very different results of the effects of membrane depolarization on the mRNA levels for the catecholamine biosynthetic enzymes were obtained depending on the osmolarity of the cultures. The extent of elevation of TH mRNA with isotonic KCl was also dependent on cell density. At high cell densities, membrane depolarization no longer induced TH mRNA levels. The results of this study indicate the experimental parameters which can be crucial in studies of membrane depolarization.
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PMID:Membrane depolarization by isotonic or hypertonic KCl: differential effects on mRNA levels of tyrosine hydroxylase and dopamine beta-hydroxylase mRNA in PC12 cells. 168 23

Both epinephrine (E) and norepinephrine (NE) cells in the rat adrenal medulla are able to proliferate in response to pharmacologic stimulation. However, previous biochemical studies have suggested that drug-induced or spontaneous pheochromocytomas in rats are almost invariably NE-producing. To resolve these apparently conflicting data, immunocytochemical techniques were utilized to establish functional profiles of adrenal medullary lesions classified as pheochromocytoma or nodular hyperplasia in rats treated chronically with a phosphodiesterase inhibitor which induced pheochromocytomas. Sixteen of 17 pheochromocytomas and all hyperplastic nodules stained positively for tyrosine hydroxylase and dopamine beta-hydroxylase, consistent with an ability to produce NE. No lesion of either type stained for phenylethanolamine N-methyltransferase, consistent with an inability to produce epinephrine. Lesions of both types showed variable staining for chromogranin proteins. The findings indicate that qualitative functional differences cannot be used to discriminate hyperplastic nodules from small pheochromocytomas in rats. Some lesions currently classified as hyperplastic nodules might in fact be small pheochromocytomas. Others might represent diffuse hyperplasia within pre-existing islands of NE-cells in a background of hyperplastic epinephrine-cells.
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PMID:Catecholamine-synthesizing enzymes and chromogranin proteins in drug-induced proliferative lesions of the rat adrenal medulla. 169 97

Site-specific analysis of tyrosine hydroxylase phosphorylation in rat pheochromocytoma led previously to the identification of a novel growth factor-sensitive serine/threonine protein kinase, designated proline-directed protein kinase (PDPK). In this article we describe further the activation, purification, subunit configuration, and biochemical characteristics of this cytoplasmic enzyme system. In human A431 epidermoid carcinoma cells PDPK activity was found to be stimulated by epidermal growth factor in a dose-dependent, time-dependent manner. The PDPK purified from the cytosol of mouse FM3A mammary carcinoma cells exhibited the same chromatographic behavior and biochemical properties as the tyrosine hydroxylase-associated enzyme purified originally from rat pheochromocytoma. The presence of p34cdc2 was ultimately detected in all active fractions of highly purified PDPK by Western blotting and immunoprecipitation; however, it was determined that this catalytic subunit is complexed with a 58-kDa regulatory subunit that is clearly distinct from that of the "growth-associated" M phase-specific histone H1 kinase (i.e. cyclin B). The 58 kDa regulatory subunit of PDPK was identified by direct immunoblotting as a mammalian A-type cyclin. Furthermore, the p58cyclin A subunit of PDPK was found to be phosphorylated on tyrosine residues in vivo and in vitro, the latter of which resulted in a significant increase in PDPK activity. Additional distinctions between this growth factor-sensitive PDPK (p34cdc2-p58cyclin A) and the M phase-specific histone H1 kinase (p34cdc2-p62cyclin B-p13suc1) are identified on the basis of chromatographic behavior, enzyme kinetics, and physicochemical properties. Based on these findings, it is proposed that PDPK represents a unique complex of the p34cdc2 protein kinase which is active in the cytoplasm of proliferative cells, is regulated differently from the M phase-specific histone H1 kinase by phosphorylation reactions, and is modulated selectively by growth factors.
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PMID:Characterization of the cytoplasmic proline-directed protein kinase in proliferative cells and tissues as a heterodimer comprised of p34cdc2 and p58cyclin A. 183 72

A suppression of norepinephrine, epinephrine, and its metabolites in malignant pheochromocytoma by metyrosine was associated with an increase in tyrosine, plasma DOPA, and sulfate esters of DOPA and dopamine, followed, with continuing metyrosine administration, by a further rise of both DOPA sulfate and dopamine sulfate. Urinary dopamine progressively increased in the course of metyrosine treatment, and this, along with the increase of the dopamine metabolite, dihydroxyphenylethanol, and plasma dopamine sulfate, occurred in the absence of any change in plasma dopamine. The octopamine metabolite para-hydroxyphenylglycol, which was initially elevated at least 10-fold, also increased after metyrosine treatment. The unexpected increase of DOPA (progressively more converted toward DOPA sulfate) in the presence of tyrosine hydroxylase inhibition and increase in tyrosine may result from channeling the excess tyrosine toward DOPA and melanin through tyrosinase. Increases in plasma dopamine sulfate and urinary dopamine suggest that dopamine sulfate may be generated via DOPA sulfate and urinary dopamine may originate from circulating DOPA. Tyrosine hydroxylase inhibition may thus result in DOPA generation in non-catecholamine-producing tissues by an alternative pathway. The resulting progressive increase in DOPA and its sulfate may lead to increased urinary dopamine. DOPA sulfate may be an alternative source of dopamine sulfate.
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PMID:Alternative catecholamine pathways after tyrosine hydroxylase inhibition in malignant pheochromocytoma. 196 15

The interaction between cell-cell contact and cyclic AMP-mediated control of the rat tyrosine hydroxylase (TH) gene was investigated in subclones of the PC12 rat pheochromocytoma cell line. Increasing cell culture density and elevation of intracellular cyclic AMP levels with forskolin both cause augmentation of TH RNA levels. However, the extent of increase in TH RNA following forskolin treatment is less in cultures grown at high density than those at low density, suggesting that there may be an interaction in the mechanism by which these two treatments modulate TH RNA levels. The role of cis-acting sequences in the TH gene in the induction of TH RNA by cyclic AMP and cell density was determined by the use of plasmid constructs containing the 5'-flanking sequences of the TH gene directing the transcription of the reporter gene, chloramphenicol acetyltransferase (CAT). Using transient transfection assays in PC12 cells, we have mapped the site of cyclic AMP regulation of the TH gene to a region between -60 and -41. Stable transformants of PC12 cells which express p5'TH CAT (-773/+27) were isolated and the activity of CAT following treatment of cells with forskolin and growth at different cell densities was evaluated. CAT activity does not differ between cells grown at low or high density. Forskolin induces CAT activity 2-4 fold, but the extent of induction does not vary with changes in cell culture density. We conclude from these experiments that the intracellular mechanism by which increased cell-cell contact modulates TH RNA levels is not through interaction with the same genomic elements as those which regulate gene expression by cyclic AMP.
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PMID:Interaction of cyclic AMP and cell-cell contact in the control of tyrosine hydroxylase RNA. 197 15

Survival period of malignant pheochromocytoma treated only conservatively is reported to be less than one year by T. Sato. A patient of malignant pheochromocytoma with liver metastasis has been treated with alpha-methyl-p-tyrosine (alpha MPT), tyrosine hydroxylase inhibitor, in the last 5 years. Catecholamine levels markedly decreased and he has a long survival time. He lives over 17 years from the detection of malignant pheochromocytoma. alpha MPT was considered to have a role to protect a patient from cardiomyopathy induced by hyper-catecholaminemia and to have the action of inhibiting the growth of this tumor. The growth of this tumor was very slow. Since this case had insulin independent diabetes mellitus, insulin therapy was applied, however, blood glucose level was not controlled well. Then we tried midaglizol (DG-5128), alpha 2-adrenoceptor antagonist, to control diabetes mellitus and a sufficient control was obtained. C-peptide level in urine was increased concomitant with decrease of blood glucose. This fact suggested that insulin secretion was improved. It is well known that catecholamine, especially noradrenaline has an inhibiting action on insulin secretion from beta cell. This action was appeared through alpha 2-adrenergic receptor. DG-5128 has an action as alpha 2-adrenoceptor antagonist. We think an inhibiting action on insulin secretion of catecholamine was diminished through its action as adrenoceptor antagonist. Kawazu et al. reported that catecholamine levels, heart rate and blood pressure did not change by DG-5128 administration in healthy subjects. In this patient, no change was appeared either. No major complication was observed during this treatment.
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PMID:[A long survived case of malignant pheochromocytoma treated with alpha-methyl-p-tyrosine and midaglizol (DG-5128)]. 197 32

We reported previously that, following phosphorylation by cyclic AMP-dependent protein kinase, tyrosine hydroxylase in rat corpus striatal extracts is inactivated in a time-dependent and apparently irreversible fashion. Removal of low molecular weight substances from these extracts by gel filtration attenuates this inactivation. We tried to determine the identity of endogenous metabolites that promote inactivation of tyrosine hydroxylase under our experimental conditions. In the present study, we report that the reducing co-substrate tetrahydrobiopterin and its analogues promoted this irreversible inactivation. The concentration that produced a 50% loss of activity (at 20 min) of the phosphorylated enzyme was 0.7 microM and that for the unphosphorylated enzyme was 420 microM. Using enzyme purified from a rat pheochromocytoma, we found that tyrosine, alpha-methyl-p-tyrosine, and a 3-iodotyrosine protected the phosphorylated enzyme against the inactivation produced by tetrahydrobiopterin. Catecholamines (dopamine, norepinephrine, epinephrine, and some of their analogues) also nullified inactivation. In contrast, the product of the reaction, dihydroxyphenylalanine, failed to attenuate the inactivation process. We performed several studies to ascertain the mechanism of inhibition by tetrahydrobiopterin. We considered the possibility that it formed reactive free radicals that produced inhibition. Free radical scavengers, however, failed to block the inhibition produced by tetrahydrobiopterin. Superoxide dismutase, catalase, and peroxidase also failed to protect tyrosine hydroxylase against inactivation. Moreover, when the experiments were performed under anaerobic conditions, the inactivation process was unaffected. These results suggest that reactive oxygenated species were not required for inactivation by tetrahydrobiopterin.
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PMID:Inactivation of tyrosine hydroxylase by pterin substrates following phosphorylation by cyclic AMP-dependent protein kinase. 197 41

Despite recommended preoperative preparation with alpha-adrenergic blockers, severe hemodynamic instability may occur during operations to resect pheochromocytoma. We combined the alpha-blocker phenoxybenzamine with the tyrosine hydroxylase inhibitor metyrosine in an attempt to better manage the hypertension of patients with pheochromocytoma undergoing surgical resection. This report reviews the cases of 25 consecutive patients undergoing surgery for known intra-abdominal pheochromocytoma. Each patient had elevated serum or urine levels of catecholamines or their metabolites. Nineteen patients were prepared before operation with phenoxybenzamine and metyrosine and six patients were given phenoxybenzamine alone. There were no significant differences in maximum, minimum, or mean blood pressure before or after tumor resection between patients who received metyrosine and those who did not. However careful review suggested that those who received metyrosine had more severe disease as judged by biochemical criteria. Study of selected patients matched for age and severity of disease suggested that the intraoperative blood pressure management of patients prepared with phenoxybenzamine and metyrosine was facilitated. In addition metyrosine-prepared patients lost less blood and required less volume replacement during surgery than did non-metyrosine-prepared patients. There were no apparent differences in postoperative fluid requirements. Although the study is not a prospective randomized trial, a retrospective review of patients managed with the combination of phenoxybenzamine and metyrosine suggests that surgery to resect pheochromocytoma can be better performed with both drugs than with phenoxybenzamine alone. The combination regimen appears to result in better blood pressure control, less blood loss, and the need for less intraoperative fluid replacement than does the traditional method of single-agent alpha-adrenergic blockade.
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PMID:Surgical management of pheochromocytoma with the use of metyrosine. 197 40


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