93 results on '"Charles A. Nichol"'
Search Results
2. Urinary excretion of bioterin and neopterin in psychiatric disorders
- Author
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Jeffrey H. Woolf, James C. Garbutt, Charles A. Nichol, Jonathan R. T. Davidson, and David S. Duch
- Subjects
Adult ,Male ,medicine.medical_specialty ,Psychosis ,Bipolar Disorder ,Urinary system ,Biopterin ,Urine ,Neopterin ,Excretion ,chemistry.chemical_compound ,immune system diseases ,Internal medicine ,mental disorders ,Humans ,Medicine ,Bipolar disorder ,Psychiatry ,Biological Psychiatry ,Depression (differential diagnoses) ,Depressive Disorder ,business.industry ,Pteridines ,Middle Aged ,medicine.disease ,Psychiatry and Mental health ,Endocrinology ,chemistry ,Schizophrenia ,Female ,business - Abstract
Levels of urinary neopterin and biopterin were determined in patients having a diagnosis of schizophrenia, unipolar depression, or bipolar depression. Both neopterin and biopterin levels were significantly higher in the urine of patients with unipolar depression than in the urine of the control group. Subclassification of patients into primary and secondary depression demonstrated a significant elevation of urinary biopterin in both groups, whereas urinary neopterin was elevated only in those patients with primary depression. In patients with bipolar depression, neopterin excretion was elevated, but biopterin excretion did not differ from controls. No significant differences were found in schizophrenic patients.
- Published
- 1984
3. Biopterin cofactor biosynthesis: GTP cyclohydrolase, neopterin and biopterin in tissues and body fluids of mammalian species
- Author
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Charles A. Nichol, David S. Duch, Jeffrey H. Woolf, and Seaton W. Bowers
- Subjects
medicine.medical_specialty ,Guinea Pigs ,Biopterin ,Hamster ,Spleen ,Urine ,Biology ,Neopterin ,General Biochemistry, Genetics and Molecular Biology ,Guinea pig ,Mice ,chemistry.chemical_compound ,Dogs ,Aminohydrolases ,Cricetinae ,Internal medicine ,medicine ,Animals ,Tissue Distribution ,General Pharmacology, Toxicology and Pharmaceutics ,GTP Cyclohydrolase ,Adrenal gland ,Pteridines ,General Medicine ,Small intestine ,Rats ,Macaca fascicularis ,medicine.anatomical_structure ,Endocrinology ,chemistry - Abstract
Levels of GTP cyclohydrolase, neopterin and biopterin were determined in tissues and body fluids of humans, monkey, dog and mouse. Highest levels of GTP cyclohydrolase and biopterin were found in pineal, liver, spleen, bone marrow, whole adrenal gland and small intestine. High levels of biopterin were found in the urine of all species examined. High levels of neopterin were found only in the urine of humans and monkeys, very low levels could be detected in dog, while none could be detected in mouse, rat, guinea pig or hamster urine.
- Published
- 1984
4. Inhibitors of histamine metabolism in vitro and in vivo
- Author
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Mark P. Edelstein, Charles A. Nichol, Cyrus J. Bacchi, and David S. Duch
- Subjects
Pharmacology ,chemistry.chemical_classification ,Histamine N-methyltransferase ,Methyltransferase ,Biochemistry ,In vitro ,chemistry.chemical_compound ,Enzyme ,chemistry ,In vivo ,Putrescine ,Diamine oxidase ,Histamine - Abstract
The effects of antimalarial and antitrypanosomal drugs on the activity of histamine N -methyl transferase and diamine oxidase in vitro , as well as diamine oxidation and histamine levels in vivo , were examined. Diamidine antitrypanosomal drugs which interfere with polyamine metabolism were found to be potent inhibitors both in vitro and in vivo . Antrycide (quinapyramine) and isometamidium were the best inhibitors of both enzymes. K i values for histamine N -methyl transferase were 3 × 10 −8 M for both compounds, and the inhibition was competitive for histamine. Antrycide and isometamidium were both non-competitive inhibitors of diamine oxidase, having K i values of 6 × 10 −9 M and 3 × 10 −9 M respectively. Isometamidium elevated histamine levels in rat kidney 2-fold and produced a long-term inhibition of putrescine oxidation in vivo . Among the compounds examined, only known active antitrypanosomal agents inhibited both histamine N -methyl transferase and diamine oxidase in vitro as well as putrescine oxidation in vivo . These observations suggest that the enzymes acting on histamine and putrescine as substrates can be used to select compounds which interfere with polyamine metabolism and that persistence of such compounds in vivo , as indicated by inhibition of putrescine oxidation, correlates with favorable chemotherapeutic properties as antitrypanosomal agents.
- Published
- 1984
5. Tetrahydrobiopterin is synthesized by separate pathways from dihydroneopterin triphosphate and from sepiapterin in adrenal medulla preparations
- Author
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Gary K. Smith and Charles A. Nichol
- Subjects
Sepiapterin ,Chemical Phenomena ,Biophysics ,Guanosine triphosphate ,Neopterin ,Biochemistry ,chemistry.chemical_compound ,Biosynthesis ,Dihydrobiopterin ,Dihydrofolate reductase ,medicine ,Animals ,Molecular Biology ,biology ,Pteridines ,Tetrahydrobiopterin ,Biopterin ,Dihydrofolate reductase inhibitor ,Pterins ,Chemistry ,Methotrexate ,medicine.anatomical_structure ,chemistry ,Adrenal Medulla ,cardiovascular system ,biology.protein ,Cattle ,Guanosine Triphosphate ,Adrenal medulla ,medicine.drug - Abstract
Using Escherichia coli guanosine triphosphate cyclohydrolase, dihydroneopterin triphosphate was synthesized from guanosine triphosphate and was compared with sepiapterin as a substrate for tetrahydrobiopterin formation in bovine adrenal medulla extracts. The dihydrofolate reductase inhibitor, methotrexate, blocks the formation of tetrahydrobiopterin from sepiapterin but not from dihydroneopterin triphosphate. Reduced nicotinamide adenine dinucleotide phosphate and a divalent metal ion are required in partially purified preparations (gel filtration of 40–60% ammonium sulfate fraction on Ultrogel ACA-34) for the biosynthesis of tetrahydrobiopterin from dihydroneopterin triphosphate. Sepiapterin was converted only to dihydrobiopterin in the same fractions since dihydrofolate reductase was removed. The evidence indicates that both dihydroneopterin triphosphate and sepiapterin are good precursors of tetrahydrobiopterin but they are not on the same pathway, contrary to previous proposals.
- Published
- 1983
6. Stimulation of retinal dopamine biosynthesis in vivo by exogenous tetrahydrobiopterin: relationship to tyrosine hydroxylase activation
- Author
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Martha M. Abou-Donia, Iuvone Pm, O.H. Viveros, John F. Reinhard, and Charles A. Nichol
- Subjects
Male ,medicine.medical_specialty ,Light ,Tyrosine 3-Monooxygenase ,genetic structures ,Dopamine ,Dark Adaptation ,Stimulation ,Endogeny ,Retina ,chemistry.chemical_compound ,In vivo ,Internal medicine ,medicine ,Animals ,Molecular Biology ,Tyrosine hydroxylase ,Pteridines ,General Neuroscience ,Rats, Inbred Strains ,Retinal ,Tetrahydrobiopterin ,Biopterin ,Dihydroxyphenylalanine ,Rats ,Enzyme Activation ,Endocrinology ,medicine.anatomical_structure ,chemistry ,sense organs ,Neurology (clinical) ,Developmental Biology ,medicine.drug - Abstract
Intravitreal injection of tetrahydrobiopterin (BH4), the cofactor for tyrosine hydroxylase (TH), increases 3,4-dihydroxyphenylalanine (DOPA) accumulation in retinas of dark-adapted rats, as does exposure to light. In contrast, BH4 had no significant effect on DOPA accumulation in retinas of light-exposed rats. The levels of endogenous retinal BH4 and the uptake of injected BH4 into the retinal tissue were not affected by light exposure. These data indicate that TH is not saturated with endogenous BH4 in the retinas of dark-adapted rats. In addition, the observations support the interpretation that the decrease in apparent Km of TH for the cofactor in response to light exposure is of sufficient magnitude to allow near saturation of TH by endogenous BH4 and, thus, is causally related to the increase of dopamine biosynthesis in response to short-term photic stimulation.
- Published
- 1985
7. Determination of biopterin and other pterins in tissues and body fluids by high-performance liquid chromatography
- Author
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Jeffrey H. Woolf, David S. Duch, and Charles A. Nichol
- Subjects
Chromatography ,Chemistry ,Pteridines ,Biopterin ,General Chemistry ,Neopterin ,High-performance liquid chromatography ,Body Fluids ,Pterins ,Xanthopterin ,Neuroblastoma ,chemistry.chemical_compound ,Humans ,Chromatography, High Pressure Liquid - Published
- 1983
8. Hormonal Regulation of Guanosine Triphosphate Cyclohydrolase Activity and Biopterin Levels in the Rat Adrenal Cortex
- Author
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Charles A. Nichol, Martha M. Abou-Donia, O H Viveros, and David S. Duch
- Subjects
Male ,medicine.medical_specialty ,Reserpine ,GTP' ,medicine.medical_treatment ,Biopterin ,Biology ,chemistry.chemical_compound ,Endocrinology ,Adrenocorticotropic Hormone ,Internal medicine ,medicine ,Animals ,Insulin ,Cycloheximide ,Sepiapterin reductase ,Hypophysectomy ,Adrenal cortex ,Pteridines ,Rats, Inbred Strains ,Tetrahydrobiopterin ,Enzyme assay ,Rats ,Kinetics ,Tetrahydrofolate Dehydrogenase ,medicine.anatomical_structure ,chemistry ,Guanylate Cyclase ,Adrenal Cortex ,biology.protein ,Cosyntropin ,medicine.drug - Abstract
The regulation of GTP-cyclohydrolase (GTP-CH) activity and tetrahydrobiopterin (BH4) levels in the adrenal cortex were studied in intact and hypophysectomized rats. Treatment with a single dose of reserpine (5 mg/kg) or insulin-induced hypoglycemia (4 h) elevated adrenocortical BH4 3-fold by 10 h; BH4 levels remained elevated after 24 h and returned to control levels by 48-72 h. GTP-CH was significantly increased 24 h after hypoglycemic shock, and the increased enzyme activity preceded the changes in BH4 levels after reserpine treatment. Two and a half hours of stress by immobilization also increased GTP-CH activity and BH4 levels in the adrenal cortex. The activities of sepiapterin reductase and dihydrofolate reductase, putative enzymes in the biosynthetic pathway from GTP to BH4, were not increased by reserpine. Both reserpine and insulin increased the apparent maximum velocity for GTP, with no increase in the affinity of the enzyme for its substrate, further suggesting that the experimental treatments induce the synthesis of GTP-CH. Hypophysectomy completely blocked the reserpine-dependent increase in both cortical GTP-CH activity and BH4 content. The administration of purified porcine ACTH to intact and hypophysectomized rats elevated adrenocortical GTP-CH activity and cofactor levels. Synthetic ACTH-(1-24) also enhanced the enzyme activity and BH4 levels in the adrenal cortex. Thus, pituitary control of adrenal cortical GTP-CH synthesis and biopterin levels appears to be mediated through the secretion of ACTH. The changes in enzyme activity and cofactor levels after activation of the hypothalamo-hypophyseal axis or ACTH administration suggest that BH4, a cofactor for certain monooxygenases, has some function, as yet unknown, in the adaptive changes of the adrenal cortex in response to stress.
- Published
- 1983
9. Metabolism of Trimethoprim in Man and Measurement of a New Metabolite: A New Fluorescence Assay
- Author
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Charles A. Nichol, Calvin M. Kunin, Carl W. Sigel, and Michael E. Grace
- Subjects
Male ,Chromatography ,Urinary system ,Metabolite ,Fluorescence assay ,Healthy subjects ,Metabolism ,Pharmacology ,urologic and male genital diseases ,bacterial infections and mycoses ,Trimethoprim ,Fluorescence ,Cyclic N-Oxides ,chemistry.chemical_compound ,Infectious Diseases ,Urinary levels ,chemistry ,Oral administration ,Methods ,medicine ,Humans ,Immunology and Allergy ,Chromatography, Thin Layer ,medicine.drug - Abstract
Urinary concentrations of trimethoprim (TMP) and its metabolites were measured in eight healthy subjects after oral administration of 160 mg of TMP in two tablets of Septra@ (trimethoprim-sulfamethoxazole). Improved procedures for extraction of polar metabolites and for enzymic cleavage of conjugated products were applied. The 1-oxide and conjugates of demethylated metabolites were found in substantially higher concentrations than those previously reported. A new metabolite, the 3-oxide of TMP, was identified, and urinary levels of this product were also measured.
- Published
- 1973
10. BIOSYNTHESIS AND METABOLISM OF TETRAHYDROBIOPTERIN AND MOLYBDOPTERIN
- Author
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Charles A. Nichol, Gary K. Smith, and David S. Duch
- Subjects
Sepiapterin ,Tyrosine 3-Monooxygenase ,Stereochemistry ,Phenylalanine ,GTP cyclohydrolase I ,Coenzymes ,Biopterin ,Tryptophan Hydroxylase ,Biochemistry ,chemistry.chemical_compound ,Biosynthesis ,Neoplasms ,Phenylketonurias ,Metalloproteins ,medicine ,Animals ,Humans ,Tissue Distribution ,GTP Cyclohydrolase ,Sepiapterin reductase ,Molybdenum ,biology ,Chemistry ,Mental Disorders ,Pteridines ,Molybdopterin ,Metabolism ,Tetrahydrobiopterin ,Body Fluids ,Pterins ,Alcohol Oxidoreductases ,Tetrahydrofolate Dehydrogenase ,Immune System Diseases ,biology.protein ,Nervous System Diseases ,Molybdenum Cofactors ,medicine.drug - Published
- 1985
11. Pharmacokinetics.Selectivity of action related to physicochemical properties and kinetic patterns of anticancer drugs
- Author
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Charles A. Nichol
- Subjects
Drug ,Cancer Research ,business.industry ,media_common.quotation_subject ,Pharmacology ,Amethopterin ,Therapeutic index ,Oncology ,Pharmacokinetics ,Cancer cell ,Cell Cycle Kinetics ,medicine ,Methotrexate ,business ,Mode of action ,media_common ,medicine.drug - Abstract
Since the therapeutic index of drugs used for the treatment of cancer is small, optimal use depends on whatever advantage can be gained by achieving an effective concentration at the critical site in the cancer cell for a period of time sufficient to kill that cell while minimizing the action on normal cells or allowing their recovery. Advances in 1) methodology for measurement of minute amounts of drugs in tissues and body fluids, 2) better understanding of cell cycle kinetics and 3) development of kinetic models and computer simulation of compartmental drug distribution now aid better choice of dosage, mode of administration and treatment schedules. Limitations on the entry of amethopterin (Methotrexate) into cells and body compartments is compared with another folate antagonist, metroprine (DDMP), having the same mode of action, yet able to penetrate into brain. CSF and amethopterin-resistant cells because of greater lipid solubility. Pharmacokinetic considerations related to the limited effectiveness of present drugs for the treatment of brain tumors lead to the concept of "compartmental chemotherapy" based on selective drug contact with tumor combined with selective protection of tissues of limiting toxicity.
- Published
- 1977
12. On the substrate specificity of bovine liver dihydrofolate reductase: New unconjugated dihydropterin substrates
- Author
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Eric C. Bigham, Gary K. Smith, Charles A. Nichol, and Sheila D. Banks
- Subjects
Stereochemistry ,Biophysics ,medicine.disease_cause ,Biochemistry ,Substrate Specificity ,Folic Acid ,Liver enzyme ,Dihydrofolate reductase ,medicine ,Animals ,Molecular Biology ,Escherichia coli ,chemistry.chemical_classification ,biology ,Pteridines ,Substrate (chemistry) ,Biopterin ,Pterins ,Kinetics ,Tetrahydrofolate Dehydrogenase ,Enzyme ,Liver ,chemistry ,biology.protein ,Substrate specificity ,Cattle - Abstract
The substrate specificity of dihydrofolate reductase from cells of different origin has been thought to be quite narrow, and unconjugated dihydropterins such as 6-methyldihydropterin are known to be very poor substrates. We have reinvestigated the substrate specificity of several dihydropterins and, in addition, have observed that in a new series of unconjugated dihydropterins of the general structure 6-CH 2 O(CH 2 ) n CH 3 several compounds are excellent substrates for the bovine liver enzyme, but none of them bind as well as dihydrofolate. The substrate activity (apparent V max ) of these compounds increases from 17 to 110% that of the natural substrate, dihydrofolate, as n is increased from 0 to 3. In contrast, these unconjugated dihydropterins are very poor substrates for the Escherichia coli enzyme.
- Published
- 1987
13. A rapid and sensitive assay for tyrosine-3-monooxygenase based upon the release of 3H2O and adsorption of [3H]-tyrosine by charcoal
- Author
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John F. Reinhard, Charles A. Nichol, and Gary K. Smith
- Subjects
Chromatography ,Aqueous solution ,Tyrosine 3-Monooxygenase ,Chemistry ,Substrate (chemistry) ,General Medicine ,Tritium ,General Biochemistry, Genetics and Molecular Biology ,Hydroxylation ,chemistry.chemical_compound ,Adsorption ,Activated charcoal ,Charcoal ,Methods ,medicine ,Animals ,Tyrosine ,General Pharmacology, Toxicology and Pharmaceutics ,Activated carbon ,medicine.drug - Abstract
A rapid, simple and sensitive assay has been developed for tyrosine-3-monooxygenase, the enzyme catalyzing the rate-limiting step in catecholamine biosynthesis. The assay is based upon the release of 3H2O from 3H-[3,5]-L-tyrosine with adsorption of the isotopic substrate (and its metabolites) by an aqueous slurry of activated charcoal. This method routinely yields low blank values and is simpler than the procedure requiring the use of cation exchange columns to separate the isotopic substrate from the 3H2O formed during the hydroxylation reaction.
- Published
- 1986
14. Prevention by polyamines of the curative effect of amicarbalide and imidocarb for Trypanosoma brucei infections in mice
- Author
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S. H. Hutner, David S. Duch, Charles A. Nichol, Cyrus J. Bacchi, and H C Nathan
- Subjects
Male ,Spermidine ,Trypanosoma brucei brucei ,Amidines ,Trypanosoma brucei ,Biochemistry ,Mice ,chemistry.chemical_compound ,Amicarbalide ,Polyamines ,medicine ,Animals ,Pharmacology ,Curative effect ,Imidocarb ,biology ,medicine.disease ,biology.organism_classification ,Trypanocidal Agents ,Virology ,Trypanosomiasis, African ,chemistry ,Female ,Spermine ,Trypanosomiasis ,Carbanilides - Published
- 1981
15. Differences in the metabolism of the aromatic amino acid hydroxylase cofactor, tetrahydrobiopterin, in mutant mice with neurological and immunological defects
- Author
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Jeffrey H. Woolf, Lois J. Maltais, David S. Duch, Charles A. Nichol, Muriel T. Davisson, and Seaton W. Bowers
- Subjects
medicine.medical_specialty ,Ratón ,Mutant ,Biopterin ,Spleen ,Anorexia ,Biology ,Biochemistry ,Mice ,Mice, Neurologic Mutants ,chemistry.chemical_compound ,Reeler ,Species Specificity ,Aminohydrolases ,Internal medicine ,Genetics ,medicine ,Aromatic amino acids ,Animals ,GTP Cyclohydrolase ,Molecular Biology ,Ecology, Evolution, Behavior and Systematics ,Brain ,General Medicine ,Tetrahydrobiopterin ,Mice, Mutant Strains ,medicine.anatomical_structure ,Endocrinology ,Immune System Diseases ,Liver ,chemistry ,medicine.symptom ,medicine.drug - Abstract
Tetrahydrobiopterin (BH4) levels and GTP cyclohydrolase activity (GTP-CH) were measured in tissues from mutants and controls of 24 different mouse strains to identify mutants that might be suitable models for diseases which are characterized by a deficiency of the biopterin cofactor, such as parkinsonism and atypical phenylketonuria. BH4 levels and GTP-CH activity were determined in brain, liver, and spleen obtained from 24 mutants with neurological or immunological defects. BH4 levels in brain were slightly but significantly decreased in only two mutants, spastic (spa) and jittery (ji), while GTP-CH activity in brain was not significantly lower than controls in any of the strains examined. GTP-CH levels in liver were significantly decreased in four mutant strains (jittery, ji; leaner, tgla; reeler, rl; and anorexia, anx); however, BH4 levels were significantly lower only in the mutant anorexia (anx). The most significant and widespread changes in both BH4 levels and GTP-CH activity were observed in spleen. In those mutants which were most affected, BH4 levels and GTP-CH activity were decreased 85-90%.
- Published
- 1986
16. Specific tlc Determination of Trimethoprim and Sulfamethoxazole in Plasma
- Author
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Charles A. Nichol, George H. Hitchings, Michael E. Grace, and Carl W. Sigel
- Subjects
Time Factors ,Chromatography ,Sulfamethoxazole ,medicine.diagnostic_test ,Chemistry ,Silica gel ,Pharmaceutical Science ,Trimethoprim ,Fluorescence ,Solutions ,Absorbance ,chemistry.chemical_compound ,Spectrophotometry ,Methods ,Solvents ,medicine ,Spectrophotometry, Ultraviolet ,Chromatography, Thin Layer ,Irradiation ,Densitometry ,medicine.drug - Abstract
A simple spectrodensitometric method for the direct determination of trimethoprim and sulfamethoxazole is based upon measurement of the absorbance of the two compounds on silica gel plates irradiated at 280 and 265 nm, respectively. Unlike the procedure for trimethoprim based on its fluorescence, which requires time for the development of the intensity of the spots, absorbance can be measured immediately. For both compounds, quantities as low as 0.005 μg can be detected and a linear relationship is observed between the integrated peak area and the amount on the plate between 0.02 and 0.5 μg. The percent recovery over the normal range of plasma concentrations for both compounds was 96–105%. This procedure for sulfamethoxazole is compared directly with a method based upon the Bratton-Marshall reaction.
- Published
- 1974
17. On the mode of action of 7-deaza-adenosine (tubercidin)
- Author
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Charles A. Nichol, Robert J. Leonard, and Alexander Bloch
- Subjects
DNA, Bacterial ,Purine ,Streptomyces tubercidicus ,Chromatography, Paper ,Stereochemistry ,Deamination ,Tritium ,Biochemistry, Genetics and Molecular Biology (miscellaneous) ,Tubercidin ,chemistry.chemical_compound ,Adenosine deaminase ,Aminohydrolases ,parasitic diseases ,Ribose ,Enterococcus faecalis ,medicine ,Pyruvates ,chemistry.chemical_classification ,Carbon Isotopes ,biology ,Nucleotides ,Nucleosides ,NAD ,Adenosine ,Streptomyces ,Anti-Bacterial Agents ,RNA, Bacterial ,Glucose ,Enzyme ,chemistry ,Biochemistry ,Glucosyltransferases ,biology.protein ,Biological Assay ,medicine.drug - Abstract
1. 1. The adenosine analog 7-deaza-adenosine (tubercidin) is an antibiotic obtained from Streptomyces tubercidicus . It inhibits the growth of Streptococcus faecalis (8043) by 50 % at a concentration of 2 · 10 −8 M. Tubercidin was not subject to cleavage by adenosine phosphorylase (EC 2.4.2.2) or to deamination by adenosine deaminase (EC 3.5.4.4). The glycosidic bond of the analog was found to be stable to acid hydrolysis. 2. 2. The antibiotic served as a substrate for numerous enzymes involved in the anabolism of adenosine, as demonstrated by its incorporation into RNA and DNA, and by the formation of nicotinamide-deaza-adenine dinucleotide. Tubercidin proved to be a weak inhibitor of adenosine phosphorylase, and interfered with the phosphorylation of adenosine and AMP. 3. 3. The inhibition of the growth of S. faecalis by tubercidin was prevented by purine and pyrimidine nucleosides, ribose 5-phosphate, pyruvate, and certain amino acids. In the presence of tubercidin, growing cultures of the test organism used pyruvate instead of glucose, whereas in the absence of the antibiotic glucose served as the main source of energy. It is suggested, therefore, that the impairment of growth is due primarily to the interference of tubercidin with the utilization of glucose.
- Published
- 1967
18. Nicotinic Acid Oxidation in Pseudomonas fluorescens
- Author
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Moritz Michaelis and Charles A. Nichol
- Subjects
chemistry.chemical_classification ,Oxidase test ,Nicotinamide ,biology ,Pseudomonas fluorescens ,Nicotinic Acids ,biology.organism_classification ,General Biochemistry, Genetics and Molecular Biology ,chemistry.chemical_compound ,Enzyme ,Hydroxylamine ,Nicotinic agonist ,chemistry ,Sodium azide ,Organic chemistry - Abstract
Summary and ConclusionThe destruction of nicotinic acid by Pseudomonas fluorescens, previously described by Koser and Baird3 was found to be an enzymic oxidation. Utilization of nicotinic acid is accompanied by oxygen uptake at a ratio of about 3 oxygen to 1 nicotinic acid. Nicotinamide is not attacked by the oxidase under our experimental conditions. Two types of inhibitors interfere with the enzymatic destruction of nicotinic acid: inhibitors of heavy metal enzymes, such as sodium azide and hydroxylamine, and surface active agents, such as octyl alcohol, toluene and lauryl pyridinium chloride. The rate of oxygen consumption indicates a destruction of the nicotinic acid molecule. Since nicotinic acid serves as a substrate and not as a co-enzyme it should be noted that this reaction sets it apart from its known function in the co-factors.
- Published
- 1947
19. INHIBITORY EFFECTS OF 4-DEOXYPYRIDOXINE ON THE ENDOGENOUS ACTIVITY AND INDUCTIOh OF TYROSINE-?-KETOGLUTARATE TRANSAMINASE BY CORTISOL
- Author
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Charles A. Nichol, Richard J. Milholland, and Fred Rosen
- Subjects
Male ,L-Serine Dehydratase ,Time Factors ,Hydrocortisone ,Antimetabolites ,Carboxy-Lyases ,Endogeny ,Pharmacology ,Inhibitory postsynaptic potential ,General Biochemistry, Genetics and Molecular Biology ,Transaminase ,Glutarates ,chemistry.chemical_compound ,Glutamates ,History and Philosophy of Science ,Adrenal Glands ,Animals ,Tyrosine ,4-Deoxypyridoxine ,Tyrosine Transaminase ,General Neuroscience ,Brain ,Caseins ,Pyridoxine ,Adrenalectomy ,Alanine Transaminase ,Rats ,Hydrazines ,Liver ,chemistry ,Enzyme Induction ,Pyridoxal Phosphate ,Ketoglutaric Acids ,Dietary Proteins ,Isonicotinic Acids ,Vitamin B 6 Deficiency - Published
- 1969
20. Glucocorticoids and Transaminase Activity
- Author
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Fred Rosen, Charles A. Nichol, Homer R. Harding, and Richard J. Milholland
- Subjects
Alanine ,biology ,Chemistry ,Adrenalectomy ,medicine.medical_treatment ,Cell Biology ,Biochemistry ,Transaminase ,Ketoglutaric Acid ,Alpha ketoglutarate ,medicine ,biology.protein ,Tyrosine ,Molecular Biology ,Hydrocortisone ,medicine.drug ,Peroxidase - Published
- 1963
21. THE SEPARATION AND DETERMINATION OF PTEROYLGLUTAMIC ACID AND RELATED COMPOUNDS
- Author
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Charles A. Nichol and Sigmund F. Zakrzewski
- Subjects
Chromatography ,Folic acid ,Biochemistry ,Chemistry ,Folic Acid Antagonists ,Cell Biology ,Pteroylglutamic acid ,Molecular Biology - Published
- 1953
22. Preparation and Biological Activity of Dihydroaminopterin*
- Author
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Maire T. Hakala, Sigmund F. Zakrzewski, and Charles A. Nichol
- Subjects
Biochemistry ,Chemistry ,Dihydroaminopterin ,Biological activity - Published
- 1962
23. STUDIES OF THE MECHANISM OF RESISTANCE TO FOLIC ACID ANALOGUES IN A STRAIN OF STREPTOCOCCUS FAECALIS
- Author
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Charles A. Nichol
- Subjects
chemistry.chemical_classification ,Strain (chemistry) ,Chemistry ,Streptococcus ,Vitamin b complex ,Cell Biology ,Ascorbic acid ,medicine.disease_cause ,Biochemistry ,Folic acid ,Folic acid analogues ,Glycine ,medicine ,Nucleotide ,Molecular Biology - Published
- 1954
24. THE INCORPORATION OF FORMATE-C14 INTO CITROVORUM FACTOR
- Author
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Sigmund F. Zakrzewski and Charles A. Nichol
- Subjects
chemistry.chemical_compound ,chemistry ,Biochemistry ,Citrovorum factor ,Formate ,Cell Biology ,Molecular Biology - Published
- 1955
25. Use of Sodium Thiosulfate as a Neutralizing Agent During Regional Administration of Nitrogen Mustard
- Author
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Imran Hatiboglu, George E. Moore, Charles A. Nichol, and Enrico Mihich
- Subjects
business.industry ,Thiosulfates ,Articles ,Pharmacology ,Sodium thiosulfate ,Nitrogen mustard ,Perfusion ,chemistry.chemical_compound ,chemistry ,Medicine ,Surgery ,Mechlorethamine ,business - Published
- 1962
26. Tetrahydrofolate Cofactors in Tissues Sensitive and Refractory to Amethopterin*
- Author
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Fred S. Rosen, Charles A. Nichol, and Hidenori Sotobayashi
- Subjects
Amethopterin ,biology ,Refractory ,Biochemistry ,Chemistry ,biology.protein ,Cofactor - Published
- 1966
27. Studies on the Mode of Action of 6-Mercaptopurine and Its Ribonucleoside on Mammalian Cells in Culture
- Author
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Maire T. Hakala and Charles A. Nichol
- Subjects
Action (philosophy) ,Chemistry ,medicine ,Cell Biology ,Pharmacology ,Ribonucleoside ,Molecular Biology ,Biochemistry ,Mercaptopurine ,medicine.drug - Published
- 1959
28. Synthesis of Citrovorum Factor From Folic Acid By Liver Slices; Augmentation By Ascorbic Acid
- Author
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Arnold D. Welch and Charles A. Nichol
- Subjects
biology ,Chemistry ,Leucovorin ,Citrovorum factor ,food and beverages ,Ascorbic Acid ,Growth ,Metabolism ,Pteroylglutamic acid ,biology.organism_classification ,Ascorbic acid ,General Biochemistry, Genetics and Molecular Biology ,Folic Acid ,Liver ,Biochemistry ,Folic acid ,Leuconostoc ,Metabolic activity ,Physiological Phenomena ,Physiological Phenomenon ,Biological Phenomena - Abstract
SummaryRat liver slices, normal or folic acid-deficient, are shown to form in the presence of pteroylglutamic acid a factor required for the growth of Leuconostoc citrovorum 8081. Ascorbic acid augments significantly the yield of the factor. The relationship of ascorbic acid to the metabolic activity of folic acid is discussed.
- Published
- 1950
29. CORTICOSTEROIDS AND TRANSAMINASE ACTIVITY: THE SPECIFICITY OF THE GLUT AMI C-PYRU VIC TRANSAMINASE RESPONSE1
- Author
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Louis E. Budnick, Nira R. Roberts, Charles A. Nichol, and Fred Rosen
- Subjects
medicine.medical_specialty ,Kidney ,Hypophysectomy ,biology ,medicine.medical_treatment ,Insulin ,Spleen ,Transaminase ,Endocrinology ,medicine.anatomical_structure ,Alanine transaminase ,Internal medicine ,medicine ,biology.protein ,Cortisone ,Testosterone ,medicine.drug - Abstract
Marked increases (2 to 5-fold) in glutamic-pyruvic transaminasc activity were observed in the livers of rats given cortisol, cortisone or several other corticosteroids subcutaneously for 4 consecutive days. Two biologically inert analogues of cortisol, 11-epicortisol and 9α-methoxycortisol acetate, were essentially inactive in this respect. Treatment with cortisol increased the activity of this transaminase markedly in thymus, liver and pancreas, to a lesser extent in kidney, and to no significant degree in spleen, muscle, heart, diaphragm, adrenal, testis and lung. The administration of adrenocorticotrophic hormone doubled the activity of glutamic-pyruvic transaminase in liver. Hypophysectomy increased the endogenous level of the transaminase in liver. Injection of cortisol elicited an increase in the activity of this transaminase in the liver of adrenalectomized or hypophysectomized rats which was similar to that observed in intact animals. Growth hormone, testosterone and insulin did not significantly ...
- Published
- 1959
30. Glucocorticosteroids and Transaminase Activity
- Author
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Charles A. Nichol, Fred Rosen, and Nira R. Roberts
- Subjects
medicine.medical_specialty ,Endocrinology ,Liver metabolism ,Gluconeogenesis ,Chemistry ,Internal medicine ,medicine ,Cell Biology ,Glutamic-Pyruvic Transaminase ,Molecular Biology ,Biochemistry ,Transaminase - Published
- 1959
31. Studies on dihydrofolate reductase related to the drug sensitivity of microbial and neoplastic cells
- Author
-
Charles A. Nichol
- Subjects
Cancer Research ,Cell division ,Receptors, Drug ,Amethopterin ,Dihydrofolate reductase ,Genetics ,medicine ,Animals ,Pediococcus ,Carcinoma 256, Walker ,Molecular Biology ,chemistry.chemical_classification ,biology ,Lymphoma, Non-Hodgkin ,Proteolytic enzymes ,Drug Resistance, Microbial ,Neoplasms, Experimental ,Rats ,Tetrahydrofolate Dehydrogenase ,Methotrexate ,Enzyme ,Biochemistry ,chemistry ,biology.protein ,Molecular Medicine ,Drug receptor ,Intracellular ,medicine.drug - Abstract
Current information about dihydrofolate reductase provides one of the most detailed models of a drug receptor yet available. The affinity of amethopterin for the substrate site of this enzyme is greater than in the case of most drug-receptor interactions. This property accounts for the retention of amethopterin for prolonged periods in the tissues of treated animals. The general properties of dihydrofolate reductase in mammalian tissues are quite similar with regard to molecular weight, cofactor requirement, substrate specificity and inhibition by 4-aminofolate antagonists. Among microorganisms, however, marked differences in the properties of this enzyme seem to reflect differences in its fine structure. Several lines of evidence indicate that there are differences in the properties of dihydrofolate reductase in different mammalian tissues which remain to be explored in relation to chemotherapy. Dihydrofolate reductase is being studied not only as a model drug receptor but also to elucidate the various factors which contribute to the selectivity for certain neoplasms of drugs known to inhibit this enzyme. In some cells capable of growing in the presence of high concentrations of amethopterin, the slow rate of drug entry, the rate of cell division and the high rate of formation of this enzyme allow sufficient dihydrofolate reductase to remain drug-free to maintain normal metabolism. The intracellular enzyme level may be regulated to some extent by the availability of substrates or cofactor since these, as well as the presence of inhibitors, confer remarkable stabilization against proteolytic digestion. Drug sensitivity is related to capacity for cellular uptake of amethopterin in both microbial and tumor systems in which factors influencing the susceptibility to inhibition of growth have been studied. A structural basis for cross sensitivity has been defined in microbial cell lines selected for increased sensitivity to amethopterin. Several diaminopyrimidines effectively inhibited an amethopterin refractory solid tumor. Marked differences in the content and distribution pattern of tetrahydrofolate cofactors in two solid tumors which differ in their response to amethopterin suggest that tissues vary with respect to the tetrahydrofolate requiring pathways most vital to their growth. The basis for the selective action of cytotoxic drugs may be elucidated by consideration of factors such as those found to be important in the selective inhibition of growth by drugs capable of inhibiting dihydrofolate reductase.
- Published
- 1968
32. Biosynthesis of Thymine and Formyltetrahydrofolate by Vitamin B12-deficient Cells of Lactobacillus leichmannii
- Author
-
Charles A. Nichol and DeWayne Roberts
- Subjects
chemistry.chemical_compound ,Biochemistry ,Biosynthesis ,chemistry ,Lactobacillus leichmannii ,Thymine metabolism ,Cell Biology ,Vitamin B12 ,Molecular Biology ,Thymine - Published
- 1962
33. Inhibition of Hepatic Alanine Transaminase Activity in Response to Treatment with 11-Deoxycorticosterone
- Author
-
Fred Rosen, Charles A. Nichol, and Homer R. Harding
- Subjects
chemistry.chemical_classification ,medicine.medical_specialty ,biology ,Chemistry ,Adrenalectomy ,medicine.medical_treatment ,Alanine Transaminase ,Response to treatment ,General Biochemistry, Genetics and Molecular Biology ,chemistry.chemical_compound ,Liver metabolism ,Enzyme ,Endocrinology ,Liver ,Alanine transaminase ,Alanine transaminase activity ,Internal medicine ,biology.protein ,medicine ,Humans ,Desoxycorticosterone ,11-Deoxycorticosterone ,Inhibitory effect ,Transaminases - Abstract
SummaryDaily administration of DOC for short periods resulted in a 60 to 70% depression in liver alanine transaminase activity. Adrenalectomy also caused a decrease in activity of alanine transaminase, but no further reduction in the level of this enzyme was observed upon treatment with DOC. Treatment with ACTH resulted in an increase in alanine transaminase activity in hypophysectomized rats, but not in adrenalectomized animals. Administration of DOC to hypophysectomized rats failed to lower alanine transaminase, nor did it alter the response of this enzyme to treatment with ACTH. The inhibitory effect of DOC on alanine transaminase activity appears to be due to suppression of ACTH release by the pituitary.
- Published
- 1961
34. THE EFFECT OF ASCORBIC ACID ON THE ENZYMATIC FORMATION OF THE CITROVORUM FACTOR
- Author
-
Charles A. Nichol
- Subjects
chemistry.chemical_classification ,Chemistry ,Citrovorum factor ,Vitamin b complex ,Cell Biology ,Glutathione ,Ascorbic acid ,Biochemistry ,chemistry.chemical_compound ,Enzyme ,Folic acid ,Molecular Biology ,Cysteine - Published
- 1953
35. Effects of pregnancy on several cortisol-responsive enzymes in rat liver
- Author
-
Charles A. Nichol, Fred Rosen, and Homer R. Harding
- Subjects
medicine.medical_specialty ,Hydrocortisone ,Thymus Gland ,Biology ,Text mining ,Pregnancy ,Physiology (medical) ,Internal medicine ,medicine ,Animals ,Progesterone ,Transaminases ,chemistry.chemical_classification ,Estradiol ,business.industry ,Proteins ,Alanine Transaminase ,medicine.disease ,Liver Glycogen ,Rats ,Enzyme ,Endocrinology ,Liver ,chemistry ,Rat liver ,Pregnancy, Animal ,Female ,business - Published
- 1966
36. Water-Soluble Vitamins Concerned with One and Two-Carbon Intermediates
- Author
-
and A D Welch and Charles A. Nichol
- Subjects
chemistry ,Water-Soluble Vitamin ,chemistry.chemical_element ,Organic chemistry ,Vitamins ,Biochemistry ,Carbon - Published
- 1952
37. Effect of Partial Hepatectomy and Pregnancy on Tumor Growth and Alanine- -Ketoglutarate Transaminase Activity
- Author
-
Charles A. Nichol, Fred Rosen, and Homer R. Harding
- Subjects
Male ,medicine.medical_specialty ,Hydrocortisone ,Endogeny ,Biology ,General Biochemistry, Genetics and Molecular Biology ,Transaminase ,Fetus ,Pregnancy ,Internal medicine ,medicine ,Animals ,Hepatectomy ,Tumor growth ,Carcinoma 256, Walker ,chemistry.chemical_classification ,Alanine ,Alanine Transaminase ,Organ Size ,medicine.disease ,Liver regeneration ,Liver Regeneration ,Rats ,Enzyme ,Endocrinology ,Liver ,chemistry ,Pregnancy, Animal ,Female - Abstract
SummaryConsequences related to the metabolic requirements for growth of new tissues during fetal development and liver regeneration were studied with regard to: 1) activity of a transaminase enzyme, alanine-α-ketoglutarate transaminase; 2) growth of Walker carcinoma 256; and 3) response of the enzyme and the tumor to treatment with cortisol. The livers of pregnant or partially hepatectomized rats did not show an increase in alanine transaminase activity after administration of cortisol at doses which produced a significant response of this enzyme in normal control animals. The growth of the Walker carcinoma 256 in partially hepatectomized rats and pregnant animals was inhibited by 40% and 80%, rspectively. While liver regeneration in tumor-bearing animals was retarded by 50%, the growing tumor had no observable effect on fetal development. Alanine transaminase activity was below normal endogenous levels in both regenerating liver and liver from pregnant rats.
- Published
- 1966
38. Evidence for a Single Enzyme Reducing Folate and Dihydrofolate
- Author
-
Charles A. Nichol and Sigmund F. Zakrzewski
- Subjects
chemistry.chemical_classification ,Enzyme ,Biochemistry ,Chemistry ,Cell Biology ,Molecular Biology - Published
- 1960
39. Resistance to Folic Acid Analogues in a Strain of Streptococcus faecalis
- Author
-
Arnold D. Welch, Sigmund F. Zakrzewski, and Charles A. Nichol
- Subjects
Strain (chemistry) ,Antimetabolites ,Biochemical Phenomena ,Chemistry ,Streptococcus ,Vitamin b complex ,medicine.disease_cause ,General Biochemistry, Genetics and Molecular Biology ,Microbiology ,Folic Acid ,Biochemistry ,Folic acid ,Folic acid analogues ,Enterococcus faecalis ,medicine ,Folic Acid Antagonists - Published
- 1953
40. Relation of Folic Acid Reductase to Amethopterin Resistance in Cultured Mammalian Cells
- Author
-
Charles A. Nichol, Maire T. Hakala, and Sigmund F. Zakrzewski
- Subjects
chemistry.chemical_classification ,Cell Biology ,Biology ,Biochemistry ,Deoxyuridine ,Amethopterin ,chemistry.chemical_compound ,Folinic acid ,Enzyme ,chemistry ,Cell culture ,medicine ,Methotrexate ,Thymidine ,Molecular Biology ,Hypoxanthine ,medicine.drug - Abstract
SUMMARY Two lines of cultured Sarcoma 180 cells resistant to amethop- terin have been studied. Resistance developed gradually in a medium containing hypoxanthine (AH cells; 67-fold resistant), and in a medium containing thymidine (AT cells; 174-fold resistant). The rate of decrease of resistance in the absence of the drug was independent of the type of medium used; after one month of cultivation, the cells were about half as resistant. The requirement for folic or folinic acids for growth was not altered during the development of resistance. Folinic acid prevented competitively the inhibition of growth caused by amethopterin; 9 times more amethopterin than folinic acid was necessary for inhibition of the growth of sensitive Sarcoma 180 cells, whereas 600 times more was necessary for inhibition of AH cells and 1500 times more for inhibition of AT cells. The relationship between folinic acid and amethopterin is discussed and a suggestion is made concerning the possible site of action involved. The sensitivity to the growth-inhibitory effects of 6-mercaptopurine, 6-diazo-5-oxo-n-norleucine, and 5-fluoro- deoxyuridine remained unchanged despite the development of amethopterin resistance. The resistant AH cells were found to contain 65 times more folic acid reductase than the sensitive Sarcoma 180 cells, and the AT cells contained 155 times more. Only the quantity of this enzyme had increased (or the number of active sites per enzyme molecule) whereas the kinetic characteristics, Michaelis constant, K,, value for folic acid (1.1 to 1.25 X 1O-5
- Published
- 1961
41. A Labile Precursor of Citrovorum Factor
- Author
-
Aaron H. Anton, Sigmund F. Zakrzewski, and Charles A. Nichol
- Subjects
Folic Acid ,Multidisciplinary ,Biochemistry ,Folic acid ,Chemistry ,Leucovorin ,Citrovorum factor ,Vitamin b complex ,Organic chemistry - Published
- 1955
42. A Case of Juvenile Pernicious Anemia: Study of the Effects of Folic Acid and Vitamin B12
- Author
-
David H. Clement, Charles A. Nichol, and Arnold D. Welch
- Subjects
Vitamin ,medicine.medical_specialty ,medicine.diagnostic_test ,Glossitis ,business.industry ,Immunology ,Physiology ,Cell Biology ,Hematology ,medicine.disease ,Ascorbic acid ,Biochemistry ,chemistry.chemical_compound ,Endocrinology ,Schilling test ,chemistry ,Internal medicine ,medicine ,Vitamin B12 ,Cyanocobalamin ,Tetrahydrofolic acid ,business ,pernicious anemia - Abstract
Observations on a 4-year-old boy with Addisonian pernicious anemia have been presented. Noteworthy clinical features included the onset of glossitis at the age of 4 months, followed by anemia severe enough to require hospitalization at the age of 1 year. Relapse occurred in the absence of specific therapy with vitamin B12 and was completely unaffected by the administration of folic acid. Studies with radioactive vitamin B12 demonstrated that almost all of the compound administered by mouth was unabsorbed and was recovered in the stools. When the vitamin was given simultaneously with a concentrate of intrinsic factor, however, approximately 70 per cent was absorbed. Furthermore, the child’s gastric juice, when mixed with radioactive vitamin B12 and fed to an adult with pernicious anemia in relapse, failed to enhance the latter’s absorption of the vitamin. The failure of our patient to absorb the vitamin alone, but his ability to do so when it was administered with intrinsic factor concentrate, was also confirmed by the "Schilling test," in which a proportion of the absorbed radioactive vitamin was "flushed" into the urine by parenteral injection of one milligram of conventional vitamin B12. Of special interest was the occurrence in the urine of an unidentified derivative of tetrahydrofolic acid, derived from orally administered pteroylglutamic acid. The presence of this compound in the urine was demonstrated chromatographically when the patient was critically ill with his disease prior to treatment with vitamin B12. Subsequent to therapy with vitamin B12, while the administration of folic acid was continued, the abnormal metabolite of folic acid could not be found in the urine. Similarly, the administration of folic acid did not lead to the appearance of this metabolite in the urine at a time when, after more than two years without specific therapy, a hematological relapse occurred that was much less severe than that previously observed. The implications of these observations, with respect to the metabolic interrelationships of folic acid and vitamin B12, are discussed. Of further interest were the findings of strongly acid gastric juice containing much mucus and free hydrochloric acid. A fairly normal gastric mucosa was demonstrated by biopsy. The meaning of these unusual findings is discussed and an hypothesis to account for them is offered. The probable sequence of events in these patients from childhood to the development of anemia, usually in later life, is set forth.
- Published
- 1961
43. Changes in alanine transaminase activity related to corticosteroid treatment or capacity for growth
- Author
-
Fred Rosen and Charles A. Nichol
- Subjects
Cancer Research ,medicine.medical_specialty ,Hydrocortisone ,Tyrosine Transaminase ,Protein metabolism ,Aspartate transaminase ,Growth ,Biology ,Transaminase ,D-Alanine Transaminase ,chemistry.chemical_compound ,Adrenocorticotropic Hormone ,Adrenal Cortex Hormones ,Transferases ,Internal medicine ,Genetics ,medicine ,Aspartate Aminotransferases ,Desoxycorticosterone ,Molecular Biology ,Progesterone ,Pharmacology ,Estradiol ,Research ,Proteins ,Alanine Transaminase ,Endocrinology ,Liver ,chemistry ,Gluconeogenesis ,Alanine transaminase ,biology.protein ,Molecular Medicine ,Vitamin B 6 Deficiency ,Glucocorticoid ,medicine.drug - Abstract
Alanine transaminase activity in liver can be increased or decreased from its normal level by various physiological conditions. The only common factor associated with these experimental treatments appears to be related to changes in the size of the amino acid pool in liver. Thus, in addition to conditions associated with an enhanced rate of gluconeogenesis, such as glucocorticoid treatment, diabetes, starvation or feeding high protein diets, each of which increases alanine transaminase activity, other conditions involving the growth of new tissues including the presence of a rapidly growing tumor, fetal development or partial hepatectomy each results in decreased activity of this transaminase in liver. Only steroids with glucocorticoid activity are effective as inducers of this transaminase. Treatments modifying pituitary-adrenal function alter the hepatic activity of alanine transaminase. Injection of corticotrophin results in elevated activity whereas injection of deoxycorticosterone consistently lowers the level of this enzyme, apparently by depression of pituitary output of ACTH. In the adrenalectomized rat, both the level of dietary protein and the presence of a corticosteroid appear to be necessary for maximal induction of alanine transaminase activity. Significant changes in alanine transaminase activity were also induced by cortisol in the thymus gland and several neoplasms responsive to this steroid. The relative change in the activity of this enzyme does appear to reflect changes in metabolism associated with the growth inhibitory effect of cortisol on such tissues. Attempts to demonstrate the induction of tyrosine transaminase in tissues other than liver have not been successful. Aspartate transaminase in liver, thymus gland or lymphocytic neoplasms is unresponsive to cortisol treatment indicating some selectivity of the adaptive response of alanine transaminase in the same tissues. Additional studies are required to determine which enzymic alterations underlie the capacity of tissues to respond to corticosteroid treatment. The alteration of alanine transaminase activity in vivo requires further study with regard to the possibility that this enzyme has a regulatory role under physiological conditions.
- Published
- 1963
44. Elevation of brain histamine levels by diaminopyrimidine inhibitors of histamine N-methyl transferase
- Author
-
Charles A. Nichol, David S. Duch, and Seaton W. Bowers
- Subjects
Brain Chemistry ,Male ,Pharmacology ,Histamine N-Methyltransferase ,Histamine N-methyltransferase ,Methyltransferase ,Chemistry ,Brain ,Methyltransferases ,In Vitro Techniques ,Biochemistry ,Rats ,Kinetics ,chemistry.chemical_compound ,Pyrimidines ,Diaminopyrimidine ,Animals ,Histamine - Published
- 1978
45. DISCUSSION
- Author
-
Morris Friedkin and Charles A. Nichol
- Subjects
History and Philosophy of Science ,General Neuroscience ,General Biochemistry, Genetics and Molecular Biology - Published
- 1971
46. Comparative growth-inhibitory activivity of homofolic acid against cell lines sensitive and resistant to amethopterin
- Author
-
Charles A. Nichol and Maire T. Hakala
- Subjects
Pharmacology ,Amethopterin ,Chemistry ,Cell culture ,Growth inhibitory ,Homofolic acid ,Biochemistry ,Molecular biology - Published
- 1966
47. ENDOCRINE AND METABOLIC REGULATION OF GTP-CYCLOHYDROLASE ACTIVITY AND TETRAHYDROBIOPTERIN LEVELS IN RAT LIVER
- Author
-
Charles A. Nichol, Martha M. Abou-Donia, Alejandro J. Daniels, O. Humberto Viveros, and Emanuel J. Diliberto
- Subjects
medicine.medical_specialty ,Endocrinology ,Metabolic regulation ,Chemistry ,Rat liver ,Internal medicine ,medicine ,Endocrine system ,Tetrahydrobiopterin ,GTP cyclohydrolase activity ,medicine.drug - Published
- 1985
48. Regulation of tetrahydrobiopterin biosynthesis in cultured adrenal cortical tumor cells by adrenocorticotropin and adenosine 3',5'-cyclic monophosphate
- Author
-
Martha A. Abou-Donia, Charles A. Nichol, Jeffrey H. Woolf, David S. Duch, O. Humberto Viveros, and Mark P. Edelstein
- Subjects
endocrine system ,medicine.medical_specialty ,Biopterin ,8-Bromo Cyclic Adenosine Monophosphate ,Stimulation ,Biology ,Cell Line ,Cyclic nucleotide ,chemistry.chemical_compound ,Mice ,Endocrinology ,Adrenocorticotropic Hormone ,Internal medicine ,medicine ,Cyclic AMP ,Hydroxyprogesterones ,Animals ,GTP Cyclohydrolase ,Progesterone ,Forskolin ,Adrenal cortex ,Pteridines ,Colforsin ,Tetrahydrobiopterin ,Adenosine ,Adrenal Cortex Neoplasms ,medicine.anatomical_structure ,chemistry ,Bucladesine ,Cell culture ,Mutation ,Cosyntropin ,hormones, hormone substitutes, and hormone antagonists ,medicine.drug - Abstract
Y-1 adrenal cortical tumor cells in culture, which contain substantial amounts of tetrahydrobiopterin [6R-(L-erythro-1',2'-dihydroxypropyl)5,6,7,8-tetrahydropterin] (BH4) and GTP cyclohydrolase (GTP-CH), were used to study the regulation of BH4 biosynthesis by ACTH and cAMP. ACTH produced a dose-dependent increase in steroidogenesis, BH4 levels and GTP-CH activity. Maximal stimulation of BH4 biosynthesis occurred at the same concentration of ACTH that caused maximal stimulation of steroidogenesis. ACTH-(1-24) was more potent than ACTH-(1-39). The stimulation of BH4 biosynthesis by ACTH was dependent on cell density, being greater at lower cell densities, but was independent of time in culture. The lack of stimulation by ACTH at higher cell densities was due to an increase in the specific activity of GTP-CH in the control cells as density increased. This increase may be due in part to the increased release of steroids, since exogenous steroids added to low density cultures also resulted in an increase in the specific activity of the enzyme. Addition of steroids had no effect on ACTH-dependent stimulation of BH4 biosynthesis at low cell densities. (Bu)2cAMP, 8-bromo-cAMP, and forskolin all produced time- and dose-dependent increases in BH4 levels, GTP-CH activity, and steroidogenesis. Maximum increases in GTP-CH and BH4 occurred at concentrations similar to those required for maximal stimulation of steroidogenesis. In the Kin-8 mutant of Y-1 cells, which has a type 1 cAMP-dependent protein kinase with an altered regulatory subunit, ACTH was unable to increase BH4 levels or GTP-CH activity at a concentration that produced maximal stimulation of BH4 and steroid biosynthesis in the parent Y-1 line. These studies indicate that Y-1 cells in culture are useful for studying the regulation of BH4 biosynthesis in the adrenal cortex.
- Published
- 1986
49. Biosynthesis of tetrahydrobiopterin by de novo and salvage pathways in adrenal medulla extracts, mammalian cell cultures, and rat brain in vivo
- Author
-
Mark P. Edelstein, Ching Lun Lee, Charles A. Nichol, David S. Duch, and John Y. Chao
- Subjects
Sepiapterin ,GTP' ,chemistry.chemical_compound ,Mice ,Cricetinae ,Dihydrofolate reductase ,medicine ,Animals ,Pterin ,Nucleotide salvage ,Cells, Cultured ,Multidisciplinary ,biology ,Chinese hamster ovary cell ,Pteridines ,Brain ,Tetrahydrobiopterin ,Biopterin ,Pterins ,Rats ,medicine.anatomical_structure ,Methotrexate ,chemistry ,Biochemistry ,Adrenal Medulla ,biology.protein ,Cattle ,Guanosine Triphosphate ,Adrenal medulla ,medicine.drug ,Research Article - Abstract
Mammalian cells and tissues were found to have two pathways for the biosynthesis of tetrahydrobiopterin (BH4): (i) the conversion of GTP to BH4 by a methotrexate-insensitive de novo pathway, and (ii) the conversion of sepiapterin to BH4 by a pterin salvage pathway dependent on dihydrofolate reductase (5,6,7,8-tetrahydrofolate: NADP+ oxidoreductase, EC 1.5.1.3) activity. In a Chinese hamster ovary cell mutant lacking dihydrofolate reductase (DUKX-B11), endogenous formation of BH4 proceeds normally but, unlike the parent cells, these cells or extracts of them do not convert sepiapterin or 7,8-dihydrobiopterin to BH4. KB cells, which do not contain detectable levels of GTP cyclohydrolase or BH4 but do contain dihydrofolate reductase, readily convert sepiapterin to BH4 and this conversion is completely prevented by methotrexate. In supernatant fractions of bovine adrenal medulla, the conversion of sepiapterin to BH4 is completely inhibited by methotrexate. Similarly, this conversion in rat brain in vivo is methotrexate-sensitive. Sepiapterin and 7,8-dihydrobiopterin apparently do not enter the de novo pathway of BH4 biosynthesis and may be derived from labile intermediates which have not yet been characterized.
- Published
- 1983
50. Utilization of dihydroflavin mononucleotide and superoxide anion for the decyclization of L-tryptophan by murine epididymal indoleamine 2,3-dioxygenase
- Author
-
Yoshisuke Ozaki, Charles A. Nichol, and David S. Duch
- Subjects
Male ,Stereochemistry ,Flavin Mononucleotide ,Biophysics ,Biochemistry ,Cofactor ,Superoxide dismutase ,5-Hydroxytryptophan ,chemistry.chemical_compound ,Mice ,Dioxygenase ,Superoxides ,FMN reductase ,Animals ,Isoelectric Point ,Indoleamine 2,3-dioxygenase ,Molecular Biology ,chemistry.chemical_classification ,Epididymis ,Mice, Inbred ICR ,biology ,Superoxide ,Superoxide Dismutase ,Tryptophan ,Hydrogen-Ion Concentration ,Catalase ,Tryptophan Oxygenase ,Kinetics ,Enzyme ,chemistry ,biology.protein ,Chromatography, Gel ,Oxygenases ,Electrophoresis, Polyacrylamide Gel ,Isoelectric Focusing - Abstract
Dihydroflavin mononucleotide (FMNH2) together with a regenerating enzyme system effectively supported l -tryptophan decyclization by indoleamine 2,3-dioxygenase isolated from murine epididymis. The native murine dioxygenase was a monomeric protein with Mr 40,000 ± 1000, an apparent pI of 4.9 ± 0.1, and an optimum pH within the range of 7 to 8. Using FMNH2 with FMN oxidoreductase, the enzyme attained significantly higher activity than the apparent maximal activity obtained by using the other electron donor systems examined (e.g., riboflavin, FAD, tetrahydrobiopterin, methylene blue). A kinetic study with the FMNH2 cofactor suggested the occurrence of a complex reaction ( l -tryptophan-FMNH2 interdependency) and a theoretical K′m of 14 μ m or a Km of 13 μ m was estimated for the substrate. l -Tryptophan 2,3-dioxygenation was competitively inhibited by l -5-hydroxytryptophan with a Ki of 1 μ m . The reaction rate was reduced to less than 50% of that of the control in the presence of Superoxide dismutase and was decreased to 3% of the control in the absence of catalase. Thus, Superoxide anion does not appear to be the only form of O2 participating in the reaction. However, these data indicate that the activation of molecular oxygen is an essential factor for an optimum catalysis and a mechanism of FMNH2-dependent oxygenation of l -tryptophan by murine indoleamine 2,3-dioxygenase.
- Published
- 1987
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