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PHEOCHROMOCYTOMA Pheochromocytoma is a disease, which seems to bear many similarities to hyperthyroidism, especially in that it seems to involve a copper deficiency. However, the key deficiency in pheochromocytoma appears to be chromium. Pheochromocytoma (or pheo for short) involves the growth of pheo tumors, which can be located in the adrenals or anywhere in the body and which produce excessive amounts of catecholamine hormones, such as epinephrine (adrenalin) and norepinephrine (noradrenalin). The effect is that the person with pheo tumors has high levels of these hormones circulating which puts the person in a constant state of extreme stress. Pheochromocytoma is usually considered a hereditary disease since it runs in families, but random occurrences exist, pointing to other possible causes. One study below is suggestive in indicating that if the father is exposed to urethane or chromium (III) before conception, the offspring may get pheochromocytoma. Besides the above theory that pheochromocytoma is the result of genetic or other damage to the father from chemical exposure, I’m also looking at the following possible disease etiology: Some minerals seem to play a role in the generation of pheochromocytoma. Excessive manganese may stimulate the growth of pheo cells and this may be a result of a chromium deficiency in pheos. High manganese foods should probably be limited. These include: bananas, blueberries, pineapples, eggs, whole grains, green vegetables, legumes, nuts, rice, eggs, and ginger. Also iron seems to be involved. Iron appears to be necessary in the formation of catecholamine hormones. Excessive manganese (or excessive cellular manganese caused by a chromium deficiency) may deplete iron, thus forcing the body to produce tumors as additional manufacturing sites for the production of catecholamine hormones. When iron is replenished, the tumors over-produce and pheo symptoms result. Copper seems to be essential for forming monoamine oxidase and other enzymes which break down the catecholamines. Since manganese is a copper antagonist, the excessive manganese causes a copper deficiency which in turn causes a depletion of monoamine oxidase and a subsequent excess of catecholamines. My interpretation of the first study below is this: Pheochromocytoma is a tumor of the chromaffin cells of the adrenal glands. Chromaffin tissue is named this from "chromium" and "affinis", which means having affinity for. The chromaffin tissue takes up and stains strongly with chromium salts. This means that these tissues normally need large amounts of chromium. In the study below, exposure of male mice to chromium before conception caused an adaptive genetic change in the offspring to prepare them for an environment where chromium levels and intake will be high. This adaptation probably increases the excretion of chromium in the offspring to prevent toxicity. However, if the offspring are then reared in a chromium-normal environment, the chromaffin cells become chromium-deficient and tumors then grow as an adaptation to increase chromium extraction from the blood supply. These tumors are pheochromocytomas and they result not from genetic "damage" but from genetic "adaptation." Other studies show that manganese, which is a chromium antagonist, increases the growth of pheo tumors, which offers further support to the thesis that pheos result from a chromium deficiency. If this analysis is correct, then pheochromocytoma may be helped significantly by supplementing with high amounts of chromium, perhaps as high as 1000 mcg or more. Please be aware that this is just a theory based upon the present studies.
Preconception urethane or chromium(III) treatment of male mice: multiple neoplastic and non-neoplastic changes in offspring. Yu W, Sipowicz MA, Haines DC, Birely L, Diwan BA, Riggs CW, Kasprzak KS, Anderson LM Division of Basic Sciences, National Cancer Institute, Frederick, Maryland, 21702, USA. Increase in neoplasia in offspring after preconception exposure of parents presents puzzling features such as high frequency of effects and lack of Mendelian inheritance. The present study examined the hypothesis that preconception carcinogenesis involves an increase in the rate of occurrence of neoplasms with a spontaneous incidence. Male NIH Swiss mice (12 per group) were exposed 2 weeks before mating (once, ip) to urethane (1.5 g/kg) or chromium(III) chloride (1 mmol/kg). Offspring (48-78/sex/group) were examined for all grossly apparent changes when moribund or at natural death, followed by histopathological diagnosis and statistical analysis. Significant exposure-related changes occurred in multiple organs. Ten to 20 percent of offspring showed changes related to paternal exposure, including at least one sired by most treated males. Pheochromocytomas occurred in both male and female offspring after both treatments, with none in controls. These neoplasms are rare in mice and suggest endocrine dysfunction as a component of preconception carcinogenesis. This was supported by increases in thyroid follicular cell and Harderian gland tumors, ovarian cysts, and uterine abnormalities. Lung tumors were increased in female offspring only. Effects seen in offspring only after paternal urethane exposure were an increase in preneoplasia/neoplasia in the glandular stomach (males) and in females, increased lymphoma but decreased incidence of histiocytic sarcoma. Increases in incidence of male reproductive gland tumors and of renal non-neoplastic lesions occurred only after chromium exposure. Thus, preconception exposure of fathers to toxicants had a significant impact on both neoplastic and non-neoplastic changes in almost all tissues in which these lesions often occur naturally during the aging process. Copyright 1999 Academic Press.
Occasional patients with medullary carcinoma of the thyroid (Multiple Endocrine Neoplasia Type II [MEN II]) are reported to have excessive serotonin (5-HT) production from the MCT; almost all patients with metastatic MCT have elevations in plasma concentration of the amine oxidase, histaminase. The elevated 5-HT production is thought to contribute to the troublesome diarrhea experienced by patients with MEN II. We compared the urinary excretion of 5-hydroxyindoleacetic acid (5-HIAA), the principle metabolite of 5-HT, of 33 patients with MCT with the urinary excretion of 5-HIAA in 33 control subjects. Six of the 33 MCT patients (18%) had severe diarrhea. The 5-HIAA excretion of the MCT patients did not differ from that of normal subjects. We also compared the platelet monoamine oxidase (MAO) activity of 27 MCT patients and 27 control subjects. The platelet MAO activity of the two groups did not differ. The 5-HT content and MAO activity of 6 of the MCTs was similar to normal thyroid tissue. The MAO activity of two follicular adenomas of the thyroid was greater than the MAO activity of MCTs. In contrast to the uniform elevation of plasma histaminase in patients with MCT, the platelet MAO activity is not altered and the majority of MCTs do not produce excessive amounts of 5-HT. My interpretation of the following study is that the high calcium intake of bulls, not counterbalanced by calcium losses which cows have from lactation, causes excess calcitonin production which leads to ultimobranchial neoplasms, multiple endocrine tumors, and pheochromocytoma. Perhaps the solution is to increase magnesium intake and limit calcium intake. Also, a copper deficiency could be involved because copper is essential for magnesium metabolism.
Klin Wochenschr 1981 Oct 15;59(20):1165-73[The influence of different diets and smoking on the clinical chemical diagnosis of pheochromocytoma, neuroblastoma, and carcinoid syndrome].[Article in German] Heinemann G, Schievelbein H, Eberhagen D, Rahlfs VThe interference of various foodstuffs on methods to determine epinephrine (E), norepinephrine (NE), vanillylmandelic acid (VMA), metanephrines (MN), homovanillic acid (HVA), and 6-hydroxyindole acetic acid (5-HIA) in the 24 h urine for diagnosis of pheochromocytoma and carcinoid syndrome, respectively, was investigated. The foodstuffs included were: tea, coffee, almonds, pineapples, cheese, walnuts, vanilla pudding, bananas, tomatoes, and chocolate. Further, the interference of cigarette smoking on the determination of E, NE, VMA, and MN was also investigated. Walnuts caused a rather high elevation of 5-HIA in the urine. After eating bananas elevated excretion of E, NE, VMA, MN, and 5-HIA was observed. Small increases of the MN values were noticed after coffee and pineapples. Smoking of 20-30 cigarettes/day had no influence on the variables measured. If the methods described are used, thus, only bananas and walnuts have to be restricted some days before and during urine sampling, but not coffee and pineapples if consumed in the usual small quantities. There is no reason to insist on diet restriction except for bananas and walnuts. PMID: 7300237, UI: 82056396 The following study shows that manganese stimulates the growth of pheochromocytoma cells.
Activation of ERK1 and ERK2 is required for manganese-induced neurite outgrowth in rat pheochromocytoma (PC12) cells. Walowitz JL, Roth JA Department of Pharmacology and Toxicology, State University of New York at Buffalo, School of Medicine and Biomedical Sciences, Buffalo 14214, USA. Mn(2+) treatment has been shown to promote neurite outgrowth in rat pheochromocytoma (PC12) cells in a time- and dose-dependent manner. This process is mediated through the interactions of extracellular matrix (ECM) proteins and integrin receptors. Studies were performed to determine whether the phosphorylation of the MAP kinases, ERK1 and 2, is required for Mn(2+)-induced neurite outgrowth. A time- and dose-dependent increase in phosphorylation of both ERK1 and 2 was observed upon treatment of PC12 cells with Mn(2+). Phosphorylation of the ERKs occurred as early as 2 hr after initiating treatment, with a maximum increase occurring at approximately 24 hr. Inhibition of MEK with the specific inhibitor, PD98059, blocked the phosphorylation of ERK1 and 2 and increased Mn(2+) toxicity. When cells were grown in serum-free defined medium, Mn(2+)-induced phosphorylation of ERK1 and ERK2 occurred in cells grown on surfaces treated with growth serum or fibronectin but not on surfaces treated with poly-L-lysine. In addition, the pentapeptide GRGDS, which blocks RGD-mediated interactions, inhibited Mn(2+)-induced phosphorylation of ERK1 and 2. The Mn(2+)-induced increase in phosphorylated ERK1 and 2 was not seen in a PC12 cell line that does not respond to Mn(2+). These data support the hypothesis that integrin-mediated activation of the MAPK signal transduction pathway leading to the activation of ERK1 and 2 is required for Mn(2+)-induced PC12 differentiation and neurite outgrowth. Copyright 1999 Wiley-Liss, Inc. PMID: 10467256, UI: 99398497
Mitochondrial manganese superoxide dismutase prevents neural apoptosis and reduces ischemic brain injury: suppression of peroxynitrite production, lipid peroxidation, and mitochondrial dysfunction. Keller JN, Kindy MS, Holtsberg FW, St Clair DK, Yen HC, Germeyer A, Steiner SM, Bruce-Keller AJ, Hutchins JB, Mattson MP Molecular and Cell Biology Division, Department of Biological Sciences, University of Kentucky, Lexington, Kentucky 40536, USA. Oxidative stress is implicated in neuronal apoptosis that occurs in physiological settings and in neurodegenerative disorders. Superoxide anion radical, produced during mitochondrial respiration, is involved in the generation of several potentially damaging reactive oxygen species including peroxynitrite. To examine directly the role of superoxide and peroxynitrite in neuronal apoptosis, we generated neural cell lines and transgenic mice that overexpress human mitochondrial manganese superoxide dismutase (MnSOD). In cultured pheochromocytoma PC6 cells, overexpression of mitochondria-localized MnSOD prevented apoptosis induced by Fe2+, amyloid beta-peptide (Abeta), and nitric oxide-generating agents. Accumulations of peroxynitrite, nitrated proteins, and the membrane lipid peroxidation product 4-hydroxynonenal (HNE) after exposure to the apoptotic insults were markedly attenuated in cells expressing MnSOD. Glutathione peroxidase activity levels were increased in cells overexpressing MnSOD, suggesting a compensatory response to increased H2O2 levels. The peroxynitrite scavenger uric acid and the antioxidants propyl gallate and glutathione prevented apoptosis induced by each apoptotic insult, suggesting central roles for peroxynitrite and membrane lipid peroxidation in oxidative stress-induced apoptosis. Apoptotic insults decreased mitochondrial transmembrane potential and energy charge in control cells but not in cells overexpressing MnSOD, and cyclosporin A and caspase inhibitors protected cells against apoptosis, demonstrating roles for mitochondrial alterations and caspase activation in the apoptotic process. Membrane lipid peroxidation, protein nitration, and neuronal death after focal cerebral ischemia were significantly reduced in transgenic mice overexpressing human MnSOD. The data suggest that mitochondrial superoxide accumulation and consequent peroxynitrite production and mitochondrial dysfunction play pivotal roles in neuronal apoptosis induced by diverse insults in cell culture and in vivo. PMID: 9425011, UI: 98086321
Remarkably suppressed manganese superoxide dismutase activity in malignant pheochromocytoma. Nakada T, Kubota Y, Sasagawa I, Yagisawa T, Watanabe M, Ishigooka M Department of Urology, Yamagata University, School of Medicine, Japan. There are almost no special histopathological characteristics or criteria that exactly define a malignant pheochromocytoma. Tissue concentrations of catecholamine metabolites and superoxide dismutase activity have been proposed as possible candidates for discriminating between benign and malignant pheochromocytomas. Tissue concentrations of dihydroxyphenylalanine, metanephrine, normetanephrine, vanillylmandelic acid, and 3-methoxy-4-hydroxyphenylethylglycol were determined in 29 normal adrenal medullas, 13 benign pheochromocytomas and 6 malignant pheochromocytomas, respectively. The copper-zinc superoxide dismutase and manganese superoxide dismutase activities in remnants of these tissues were determined by interruption of nitric formation from hydroxylamines. Catecholamine metabolites and copper-zinc superoxide dismutase activity in benign and malignant pheochromocytomas were identical. Manganese superoxide dismutase activity in malignant pheochromocytoma was the lowest among the groups examined. These data suggest that the assay of catecholamine metabolites in removed specimens is not a reliable method for making a differential diagnosis of benign or malignant pheochromocytoma. However, a low level of manganese superoxide dismutase activity in malignant pheochromocytoma may be a marker for malignancy of this neoplasm. PMID: 7752317, UI: 95271750
Manganese induces spreading and process outgrowth in rat pheochromocytoma (PC12) cells. Lin WH, Higgins D, Pacheco M, Aletta J, Perini S, Marcucci KA, Roth JA Department of Pharmacology and Therapeutics, School of Medicine and Biomedical Science, State University of New York, Buffalo. Mn2+ has been shown to promote cell-substrate adhesion and cell spreading in many cell culture systems. In this study, we present data demonstrating that Mn2+ not only promotes spreading, but also induces process outgrowth in rat pheochromocytoma (PC12) cells. In the presence of 1.0 mM MnCl2, cell spreading was apparent by 6 hr, and nearly 50% of the exposed cells extended neurite-like processes. These morphological effects of Mn2+ were both time- and dose-dependent. In the presence of cycloheximide, a protein synthesis inhibitor, both Mn(2+)-induced spreading and neurite outgrowth were prevented, indicating that de novo protein synthesis is required for the effects of Mn2+ to take place. Of the other divalent cations tested, Mg2+, Cd2+, Cu2+, Ni2+, and Zn2+ were ineffective, and only Co2+ partially mimicked the effects of Mn2+. Although Mn(2+)-induced cell adhesion and spreading have been extensively studied, this is the first report that this divalent cation can cause neurite outgrowth. The neurite outgrowth-promoting effects of Mn2+ were distinct from those of nerve growth factor in that the response to Mn2+ was considerably more rapid, but apparently lacked the ability to sustain continuous outgrowth and networking of neurites. Mn2+ also induced the levels of GAP-43 and peripherin, two proteins associated with neuronal differentiation of PC-12 cells. In cells grown in serum-free defined medium, Mn2+ was capable of promoting neurite outgrowth when the cells were plated on surfaces pretreated with normal growth medium, vitronectin, or fibronectin, while it failed to cause these morphological changes in cells plated on untreated or poly-D-lysine-coated substrata. Similarly, Mn2+ also promoted neurite outgrowth from rat sympathetic neurons attached to laminin-treated substrate, but had no effect on neurons maintained on substrate with polylysine only. The pentapeptide Gly-Arg-Gly-Asp-Ser nearly completely prevented the morphological effects of Mn2+ on PC12 cells. These findings are consistent with a hypothesis that Mn(2+)-mediated alteration of an RGD-dependent extracellular matrix-integrin interaction is responsible for the neuritogenic effects.
Dopamine metabolism alterations in a manganese-treated pheochromocytoma cell line (PC12). Vescovi A, Facheris L, Zaffaroni A, Malanca G, Parati EA Laboratory of Cellular Neuropharmacology, National Neurological Institute C. Besta, Milan, Italy. By monitoring dopamine metabolism in rat pheochromocytoma derived PC12 cell cultures during extended treatment with manganese chloride, we assessed the functional changes occurring in a dopaminergic system during the development of manganese-induced damage. Besides eliciting a specific toxic effect on PC12 cells, manganese induced the complete disappearance of extracellular (free) but not intracellular (vesicle stored) dopamine and its metabolite 3,4-dihydroxyphenylacetic acid. This effect was observed also using low manganese concentrations (1 microM) and mainly occurred by non-enzymatic catechol oxidation since it was still evident in a cell free medium and it was fully prevented by ascorbic acid but not by reduced glutathione. The possibility of a mere "non-biological" action was ruled out by the observation of an irreversible effect of manganese as manifested by the cells' apparent inability to release dopamine or 3,4-dihydroxyphenylacetic acid into the culture medium even after complete manganese removal (post-manganese incubation). That a free radical mechanism was not involved in the genesis of this irreversible effect was shown by the fact that neither ascorbic acid, catalase, superoxide dismutase nor glutathione-peroxidase were able to prevent the decrease in catecholamine levels in the "post-manganese" incubation medium when added at the same time as the manganese. The results establish this PC12 cell system as an in vitro model for studying interactions between manganese and catechols and provide a detailed description of the nature of the neurochemical alterations that this heavy metal can induce in a dopaminergic system. PMID: 2031248, UI: 91233477
Low level of superoxide dismutase activity in pheochromocytoma. Nakada T, Koike H, Katayama T A copper-zinc superoxide dismutase found in the cytosol and intermembrane space of mitochondria, and a manganese superoxide dismutase detected in the mitochondria were determined in pheochromocytomas and normal adrenal tissues. Manganese superoxide dismutase activity in pheochromocytomas was lower than that in the normal adrenal tissues but copper-zinc superoxide dismutase activity was almost identical. The total catecholamine content in pheochromocytomas was greater than that in the normal adrenal tissues, and negative relationships were noted between superoxide dismutase activities and total catecholamine content in pheochromocytomas alone. The low level of manganese superoxide dismutase activity might be a characteristic of pheochromocytomas and the decrease in manganese superoxide dismutase activity may not be attributed solely to a decrease in the amount of mitochondria but to a nonspecific abnormality in mitochondrial enzymes.
Dopamine and iron induce apoptosis in PC12 cells. Velez-Pardo C, Jimenez Del Rio M, Verschueren H, Ebinger G, Vauquelin G Department of Protein Chemistry, Free University Brussels (VUB), Belgium. Recent studies have shown that Fe2+ increases the oxidation of monoamines such as serotonin, dopamine and related toxins and that the formed oxidation products can undergo co-valent binding to free sulphydryl groups of proteins such as actin and "serotonin binding proteins" which are present in soluble brain extracts. Here we have tested the ability of ferrous iron to induce [3H]dopamine association to cytoplasmic proteins and we have established that a similar oxidation mechanism evidenced in vitro studies could be applied in cell culture. When PC12 cells were incubated with ferrous iron (ferrocene), the binding of [3H]dopamine to proteins was found to be two fold increased with respect to control. The iron is likely to accelerate the oxidation of dopamine to produce quinones which covalently bind to proteins and induce high-molecular protein aggregates. We evidenced that dopamine/iron combination induced cell death in undifferentiated PC12 cells via an active cellular process evaluated in terms of morphological and biochemical changes indicative of apoptosis. We also demonstrated induction of lipid peroxidation when dopamine and ferrocene were present in high concentrations. Moreover, ascorbic acid diminished apoptosis but not the lipid peroxidation process. It might indicate that ferrocene and dopamine could produce oxidative stress of a different nature. These results show that the actions of dopamine and iron are essential in the induction of apoptosis and lipid peroxidation. However, there is no necessary casual link between lipid peroxidation and apoptosis. Our data also suggest that iron is capable of increasing the cytotoxicity of dopamine merely by increasing its rate of oxidation and without intervention of the monoamine oxidase B enzyme and, hence, both phenomenons may occur independently from each other in rat pheochromocytoma PC12. These observations may have relevance to the understanding of the mechanism by which dopaminergic neurones are destroyed in some neurodegenerative disorders. PMID: 9060038, UI: 97213273
Occasional patients with medullary carcinoma of the thyroid (Multiple Endocrine Neoplasia Type II [MEN II]) are reported to have excessive serotonin (5-HT) production from the MCT; almost all patients with metastatic MCT have elevations in plasma concentration of the amine oxidase, histaminase. The elevated 5-HT production is thought ot contribute to the troublesome diarrhea experienced by patients with MEN II. We compared the urinary excretion of 5-hydroxyindoleacetic acid (5-HIAA), the principle metabolite of 5-HT, of 33 patients with MCT with the urinary excretion of 5-HIAA in 33 control subjects. Six of the 33 MCT patients (18%) had severe diarrhea. The 5-HIAA excretion of the MCT patients did not differ from that of normal subjects. We also compared the platelet monoamine oxidase (MAO) activity of 27 MCT patients and 27 control subjects. The platelet MAO activity of the two groups did not differ. The 5-HT content and MAO activity of 6 of the MCTs was similar to normal thyroid tissue. The MAO activity of two follicular adenomas of the thyroid was greater than the MAO activity of MCTs. In contrast to the uniform elevation of plasma histaminase in patients with MCT, the platelet MAO activity is not altered and the majority of MCTs do not produce excessive amounts of 5-HT.
Natl Toxicol Program Tech Rep Ser 2001
Jul;499:1-343
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