Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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Vitamins contain reactive functional groups necessary to their established roles as coenzymes and reducing agents. Their reactive potential may produce injury if vitamin concentration, distribution, or metabolism is altered. However, identification of vitamin toxicity has been difficult. The only well-established human vitamin neurotoxic effects are those due to hypervitaminosis A (pseudotumor cerebri) and pyridoxine (sensory neuropathy). In each case, the neurological effects of vitamin deficiency and vitamin excess are similar. Closely related to the neurological symptoms of hypervitaminosis A are symptoms including headache, pseudotumor cerebri, and embryotoxic effects reported in patients given vitamin A analogs or retinoids. Most tissues contain retinoic acid (RA) and vitamin D receptors, members of a steroid receptor superfamily known to regulate development and gene expression. Vitamin D3 effects on central nervous system (CNS) gene expression are predictable, in addition to the indirect effects owing to its influence on calcium and phosphorus homeostasis. Folates and thiamine cause seizures and excitation when administered in high dosage directly into the brain or cerebrospinal fluid (CSF) of experimental animals but have rarely been reported to cause human neurotoxicity, although fatal reactions to i.v. thiamine are well known. Ascorbic acid influences CNS function after peripheral administration and influences brain cell differentiation and 2-deoxyglucose accumulation by cultured glial cells. Biotin influences gene expression in animals that are not vitamin-deficient and alters astrocyte glucose utilization. The multiple enzymes and binding proteins involved in regeneration of retinal vitamin A illustrate the complexity of vitamin processing in the body. Vitamin A toxicity is also a good general model of vitamin neurotoxicity, because it shows the importance of the ratio of vitamin and vitamin-binding proteins in producing vitamin toxicity and of CNS permeability barriers. Because vitamin A and analogs enter the CNS better than most vitamins, and because retinoids have many effects on enzyme activity and gene expression, Vitamin A neurotoxicity is more likely than that of most, perhaps all other vitamins. Megadose vitamin therapy may cause injury that is confused with disease symptoms. High vitamin intake is more hazardous to peripheral organs than to the nervous system, because CNS vitamin entry is restricted. Vitamin administration into the brain or CSF, recommended in certain disease states, is hazardous and best avoided. The lack of controlled trials prevents us from defining the lowest human neurotoxic dose of any vitamin. Large differences in individual susceptibility to vitamin neurotoxicity probably exist, and ordinary vitamin doses may harm occasional patients with genetic disorders.(ABSTRACT TRUNCATED AT 400 WORDS)
Mol Neurobiol 1992
PMID:Vitamin neurotoxicity. 146 88

Ascorbic acid (AH2) is a potential scavenger of superoxide radical and singlet oxygen. In the guinea pig, marginal AH2 deficiency results in intracellular oxidative damage in the cardiac tissue as evidenced by lipid peroxidation, formation of fluorescent pigment and loss of structural integrity of the microsomal membranes. The oxidative damage does not occur due to lack of enzymatic scavengers of reactive oxygen species such as superoxide dismutase, catalase and glutathione peroxidase. Also, glutathione transferase activity is not decreased in AH2 deficiency. Lipid peroxidation, fluorescent pigment formation and protein modification disappear after AH2 therapy. These results, if extra-polated to human beings, would indicate that chronic subclinical AH2 deficiency may result in progressive oxidative damage which in the long run may lead to permanent degenerative diseases in the heart.
Mol Cell Biochem 1992 Apr
PMID:Protective role of ascorbic acid against lipid peroxidation and myocardial injury. 158 41

Ascorbic acid (VC) deficiency resulted in a decrease in the activities of aminopyrine N-demethylase, aniline hydroxylase, and p-nitroanisole O-demethylase and in the content of cytochrome P-450, as spectrally determined, whereas it caused an increase in the activities of 6 beta-hydroxylases for testosterone and progesterone in liver microsomes of guinea pigs. Western blot analysis of liver microsomes with antibodies to rat P-448-H (P-4501A2), P-450j (P-450IIE), P-450 PB-1 (P-450IIIA), and P-450b (P-450IIB1) showed that VC deficiency decreased the amount of cytochrome P-450 immunochemically related to P-450IA2 and P-450IIE but did not change the amount of the form that was cross-reactive with antibodies to P-450IIB1 and tended to slightly increase (not statistically significantly) the amount of the form of the cytochrome immunochemically related to P-450IIIA. The larger decrease by VC deficiency in the amount of cytochrome P-450 that was cross-reactive to the rat P-450IA2 resulted in a lower capacity of liver microsomes to activate promutagens, such as 2-amino-3-methyl-imidazo(4,5-f)quinoline and aflatoxin B1. These results indicate that VC deficiency in guinea pigs differentially affects the content of individual forms of cytochrome P-450.
Mol Pharmacol 1991 Apr
PMID:Ascorbic acid deficiency decreases specific forms of cytochrome P-450 in liver microsomes of guinea pigs. 190 38

Pretreatment of cultured hepatocytes with the ferric iron chelator deferoxamine prevents the killing of the cells by tert-butyl hydroperoxide (TBHP). Incubation of the deferoxamine-pretreated hepatocytes in a serum-free medium containing only 0.25 nM iron restored the sensitivity of the cells to TBHP within 4 to 6 hr. An amino acid-free medium accelerated the restoration of sensitivity in parallel with an enhanced rate of degradation of 14C-prelabeled protein. By contrast, inhibitors of the autophagic degradation of protein, including chymostatin, 3-methyladenine, benzyl alcohol, colchicine, oligomycin, and methylamine, inhibited the restoration of sensitivity of deferoxamine-treated hepatocytes to TBHP in parallel with their inhibition of protein degradation. With chymostatin, 3-methyladenine, benzyl alcohol, and colchicine, there was a parallel dose dependency of both the inhibition of protein turnover and the inhibition of the restoration of sensitivity to TBHP. Ascorbic acid, known to specifically retard the autophagic degradation of ferritin, inhibited the restoration of sensitivity to TBHP without effect on the general rate of protein turnover. None of the agents studied had any protective effect on the toxicity of TBHP for hepatocytes that were not pretreated with deferoxamine. These data indicate that the autophagic degradation of protein generates a pool of ferric iron required for the killing of cultured hepatocytes by TBHP.
Mol Pharmacol 1990 Mar
PMID:Autophagic degradation of protein generates a pool of ferric iron required for the killing of cultured hepatocytes by an oxidative stress. 231 91

Ferric ion was found to stimulate the peroxidation of erythrocyte membrane lipids, causing a biphasic and concentration-dependent increase in the formation of thiobarbituric acid reactive substances. Ascorbic acid and reduced glutathione were able to enhance this lipid peroxidation, presumably by facilitating the reduction of ferric ion. Iron chelators, such as phytic acid, ethylenediaminetetraacetic acid and uric acid, and the chain-reaction-terminating antioxidant butylated hydroxytoluene suppressed the ferric ion-induced peroxidation by actions not likely related to hydroxyl radical scavenging. The effectiveness of phytic acid, a naturally occurring antioxidant, in the inhibition of iron-dependent lipid peroxidation suggests its possible therapeutic application as a non-toxic iron chelator for ameliorating the extent of oxy-radical-induced tissue damage.
Mol Cell Biochem 1990 Jun 25
PMID:Ferric ion-induced lipid peroxidation in erythrocyte membranes: effects of phytic acid and butylated hydroxytoluene. 236 55

2-Bromo-(diglutathion-S-yl)hydroquinone [2-Br-(diGSyl)HQ] causes severe necrosis of the proximal renal tubules in the rat, elevations in blood urea nitrogen (BUN) and increased urinary excretion of protein, glucose, and lactate dehydrogenase. In contrast, 2-Br-3-(GSyl)HQ, 2-Br-5-(GSyl)HQ, and 2-Br-6-(GSyl)HQ caused differentially less toxicity than the diglutathionyl conjugate. None of these conjugates had any apparent effect on liver pathology and serum glutamate-pyruvate transaminase remained within the normal range. Pretreatment of rats with probenecid, an organic anion transport inhibitor, offered only slight protection against 2-Br-(diGSyl)HQ-mediated elevations in BUN, proteinuria, or glucosuria. In contrast, quinine, an organic cation transport inhibitor, potentiated the nephrotoxicity of 2-Br-(di-GSyl)HQ. Thus, in contrast to other nephrotoxic sulfur conjugates, probenecid-sensitive organic ion transport systems do not contribute to the kidney-specific toxicity of 2-Br-(diGSyl)HQ. However, inhibition of renal gamma-glutamyl transpeptidase by AT-125 completely protected rats from the nephrotoxic effects of 2-Br-(diGSyl)HQ. Aminooxyacetic acid, an inhibitor of cysteine conjugate beta-lyase, caused a 20-25% decrease in 2-Br-(diGSyl)HQ-mediated elevations in BUN and urinary excretion parameters. The isomeric 35S conjugates covalently bound to rat kidney 10,000 x g homogenate in the order 2-Br-6-(GSyl)HQ greater than 2-Br-5-(GSyl)HQ greater than 2-Br-3-(GSyl)HQ greater than 2-Br-(diGSyl)HQ. AT-125 (0.4 mM) decreased covalent binding by 25%, 17%, 33%, and 28%, respectively. Aminooxyacetic acid (0.1 mM) inhibited covalent binding by 26%, 10%, 17%, and 17% respectively. Ascorbic acid (1.0 mM) inhibited covalent binding by 63%, 87%, 62%, and 28%, respectively, and this inhibition correlated, inversely, with the redox potential of the conjugates. Thus, the covalent binding is mediated preferentially by oxidation of the quinol moiety, although the formation of reactive thiols cannot be excluded. In addition, the initial conjugation of 2-BrHQ with GSH does not result in the formation of a less redox-active species. However, the subsequent addition of a second molecule of GSH results in the formation of a more redox-stable compound, which, paradoxically, enhances toxicity. The metabolism of 2-Br-(diGSyl)HQ by renal proximal tubular gamma-glutamyl transpeptidase and trans-membrane transport of the cysteine conjugate(s) followed by oxidation of the quinol moiety is probably responsible for the target organ toxicity of this compound.
Mol Pharmacol 1988 Oct
PMID:2-Bromo-(diglutathion-S-yl)hydroquinone nephrotoxicity: physiological, biochemical, and electrochemical determinants. 317 33

The human caudate and putamen contain two high affinity binding sites for [3H]spiroperidol. Both of these affinity states exhibit dopaminergic selectivity. Ascorbic acid, at 0.1 mM, induces a slow loss of the low affinity component of [3H]spiroperidol binding in these tissues. The addition of guanyl nucleotides to the ascorbate produces a more rapid loss of [3H]spiroperidol binding which includes a loss of the highest affinity state for [3H]spiroperidol. Ascorbate induces lipid peroxidation in human caudate and putamen, an effect that is further enhanced by guanyl and inosine nucleotides. In the absence of ascorbate, guanyl nucleotides have no effect on [3H]spiroperidol binding but do decrease the affinity of dopamine at each affinity state greater than 60-fold. In the absence of ascorbate, guanyl nucleotides apparently decrease agonist affinity at human brain dopamine2-binding sites without causing an interconversion of agonist affinity states.
Mol Pharmacol 1988 Feb
PMID:Guanyl nucleotide interactions with dopaminergic binding sites labeled by [3H]spiroperidol in human caudate and putamen: guanyl nucleotides enhance ascorbate-induced lipid peroxidation and cause an apparent loss of high affinity binding sites. 334 80

We have demonstrated in rat adrenal (Natarajan, R.D. and Harding, B.W. (1985) J. Biol. Chem. 260, 3902-3905) that NADH-semidehydroascorbate reductase and ascorbate participate in an electron transport pathway (ETP) supplying reducing equivalents from NADH to cytochrome P-450scc. Here, we demonstrate that this ascorbate dependent ETP also supplies reducing equivalents to cytochrome P-450(11 beta/18) in both rat adrenal and bovine adrenal cortex. The activity is dependent upon addition of catalase or upon 'cold shock' treatment of isolated mitochondria. Comparison of the rates of 11 beta- and 18-hydroxylation supported by this ETP and by the classical pathway supported by various TCA cycle intermediates suggests that in vivo the ascorbate dependent pathway may be essential for maximal flow of reducing equivalents to the mitochondrial hydroxylases. Partial reconstitution of the ascorbate dependent 11 beta/18-hydroxylase activity was achieved with purified bovine outer mitochondrial and inner mitochondrial membranes fortified with supernatant from sonified mitochondria all preincubated with phosphatidyl choline. These preparations no longer require catalase or 'cold shock' treatment. Ascorbate and NADH-semidehydroascorbate reductase are unable to support 17 alpha- or 21-hydroxylase activity in isolated bovine adrenal cortical microsomes whether incubated with purified outer mitochondrial membranes or not.
Mol Cell Endocrinol 1987 Sep
PMID:The function of NADH-semidehydroascorbate reductase and ascorbic acid in corticosteroid hydroxylation. 366 95

Ascorbic acid uptake in AtT-20 tumor cells and primary cultures of rat anterior and intermediate pituitary was sodium-dependent and showed half-maximal saturation between 9 and 18 microM ascorbate. When incubated in [14C]ascorbic acid at concentrations similar to those in serum (50 microM), all of the cells concentrated ascorbate 20- to 40-fold, producing intracellular ascorbate concentrations of 1-2 mM. HPLC analyses showed that over 90% of the intracellular label comigrated with authentic ascorbic acid. Although ascorbate was rapidly oxidized in culture medium in the absence of cells, incubation of ascorbate in culture medium in the presence of cells stabilized the ascorbate substantially. Unlike systems that transport dehydroascorbic acid, the ascorbate transport systems in all three preparations were not inhibited by glucose. Thus all three systems possess similar saturable, high-affinity, sodium-dependent active transport systems for ascorbic acid.
Mol Cell Endocrinol 1986 Dec
PMID:Transport and stability of ascorbic acid in pituitary cultures. 380 8

We have reported previously that toxic concentrations of isoproterenol caused severe alterations in the structural integrity of the sarcolemma and mitochondria found in primary cultures of rat myocardial cells [8, 9]. Mitochondrial injury was observed 1.5 h after exposure to isoproterenol, whereas leakage of intracellular ions and enzymes was observed only after prolonged exposures (greater than 4 h). Ascorbic acid and sodium bisulfite prevented the cytotoxic effects of isoproterenol in our cell culture system. Takeo et al. [13] suggested that adrenochrome (an oxidative metabolite of epinephrine) specifically inhibits the activity of the sodium/potassium ATPase. Other investigators have shown that an indole metabolite of epinephrine inhibited actomyosin ATPase [1, 4]. These inhibitory actions may result from an interaction between the oxidative metabolites and sulfhydryl groups present in the enzyme [13]. Inhibition of the sodium/potassium ATPase is associated with an increase in the intracellular concentration of Na+ and Ca2+ and a decrease in intracellular K+. Changes in the intracellular concentration of these ions are commonly seen in heart cell damage and contractile failure [2]. The present study was designed to determine if isoproterenol, a synthetic catecholamine, inhibits the sodium/potassium ATPase activity in a primary culture system of rat myocardial cells.
J Mol Cell Cardiol 1984 Mar
PMID:Attenuation by antioxidants of Na+/K+ ATPase inhibition by toxic concentrations of isoproterenol in cultured rat myocardial cells. 632 17


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