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PubMed1986

Nuclear magnetic resonance spectroscopy and imaging in the study of experimental liver diseases.

We are investigating potential noninvasive new strategies for the assessment of liver injury, steatosis, and hepatic tumor development. These techniques employ nuclear magnetic resonance (NMR) imaging and spectroscopy. Accordingly, several experimental animal models of liver injury and steatosis produced in rats by ethanol, azaserine, L-ethionine, carbon tetrachloride, and D-galactosamine. Ethanol and L-ethionine induce acute steatosis without necrosis, whereas azaserine, carbon tetrachloride, and D-galactosamine are known to produce steatosis with varying degrees of hepatic necrosis. Triglyceride content and protein spin relaxation times were measured. T1 values were analyzed by using an inversion recovery technique at eight different tau values (20 msec to 2.50 sec) and T2 by Carr-Purcell-Meibloom-Gill pulse sequences with 10 spin echoes (4-40 msec). We also performed NMR imaging studies on controls and ethanol-induced steatosis using a 60-MHz Technicare 8-cm bore superconducting system. Results of these experiments indicate that varying degrees of steatosis produce striking changes in T2 without inducing changes in T1, whereas necrosis superimposed on steatosis produces T1 changes as well. Thus, these NMR spectroscopy and imaging studies demonstrated that steatosis may be clearly defined in vitro and in vivo.

Animals↗
PubMed2001

In vivo regulation of glutamine synthetase activity in the marine chlorophyll b-containing cyanobacterium Prochlorococcus sp. strain PCC 9511 (oxyphotobacteria).

The physiological regulation of glutamine synthetase (GS; EC 6.3.1.2) in the axenic Prochlorococcus sp. strain PCC 9511 was studied. GS activity and antigen concentration were measured using the transferase and biosynthetic assays and the electroimmunoassay, respectively. GS activity decreased when cells were subjected to nitrogen starvation or cultured with oxidized nitrogen sources, which proved to be nonusable for Prochlorococcus growth. The GS activity in cultures subjected to long-term phosphorus starvation was lower than that in equivalent nitrogen-starved cultures. Azaserine, an inhibitor of glutamate synthase, provoked an increase in enzymatic activity, suggesting that glutamine is not involved in GS regulation. Darkness did not affect GS activity significantly, while the addition of diuron provoked GS inactivation. GS protein determination showed that azaserine induces an increase in the concentration of the enzyme. The unusual responses to darkness and nitrogen starvation could reflect adaptation mechanisms of Prochlorococcus for coping with a light- and nutrient-limited environment.

Adaptation, Physiological↗
PubMed1987

Nitrogen starvation mediated by DL-7-azatryptophan in the cyanobacterium Anabaena sp. strain CA.

The addition of DL-7-azatryptophan (AZAT), a tryptophan analog, to continuous cultures of Anabaena sp. strain CA grown with 10 mM nitrate as the nitrogen source resulted in the differentiation of heterocysts. Analysis of the intracellular amino acid pools of Anabaena sp. strain CA after the addition of AZAT showed a marked decline in the intracellular glutamate pool and a slight increase in the levels of glutamine. The in vitro activity of glutamate synthase, the second enzyme involved in primary ammonia assimilation in Anabaena spp., was partially inhibited by the presence of AZAT at concentrations which are effective in triggering heterocyst formation (15% inhibition at 10 microM AZAT and up to 85% inhibition at 1.0 mM AZAT). Azaserine, a glutamine analog and potent glutamate synthase inhibitor, had no effect on the triggering of heterocyst development from undifferentiated batch and continuous cultures of Anabaena sp. strain CA. However, the presence of 1.0 microM azaserine significantly decreased the intracellular glutamate pool and increased the glutamine pool. The addition of AZAT also caused a decrease in the C-phycocyanin content of Anabaena sp. strain CA as a result of its proteolytic degradation. AZAT also had an inhibitory effect on the nitrogenase activity of Anabaena sp. strain CA. All these results suggest that AZAT causes a general nitrogen starvation of Anabaena sp. strain CA filaments, triggering heterocyst synthesis.

Acetylene↗
PubMed2004

Hexosamine pathway is responsible for inhibition by diabetes of phenylephrine-induced inotropy.

Hyperglycemia diminishes positive inotropic responses to agonists that activate phospholipase C (PLC) and generate inositol trisphosphate (1,4,5). The mechanisms underlying both the inotropic responses and hyperglycemia's effects on them remain undetermined, but data from isolated cardiomyocytes suggest the involvement of capacitative Ca(2+) entry (CCE), the influx of Ca(2+) through plasma membrane channels activated in response to depletion of endoplasmic or sarcoplasmic reticulum Ca(2+) stores. In neonatal rat cardiomyocytes, hyperglycemia decreased CCE induced by PLC-mediated agonists. The attenuation of CCE was also seen with glucosamine, and the inhibition by hyperglycemia was prevented by azaserine, thereby implicating hexosamine biosynthesis as the responsible metabolic pathway. In the current study, the importance of hexosamine metabolites to hyperglycemia's effects on inotropic responses was examined in isolated perfused rat hearts. The inhibition by hyperglycemia of phenylephrine-induced inotropy was reversed with azaserine and mimicked by glucosamine. An independent inhibitor of CCE, SKF96365, was also effective in blunting inotropy. These treatments did not inhibit inotropy induced by activation of adenylate cyclase through beta-adrenergic receptors. These data thus implicate CCE in responses to PLC-mediated agonists in the intact heart and point to the hexosamine pathway's negative effect on CCE as being central to the inhibition seen with hyperglycemia.

Animals↗
PubMed1989

Inhibition of a transplantable pancreatic carcinoma by castration and estradiol administration in rats.

Influence of sex steroids on the growth of an azaserine-induced transplantable rat pancreatic carcinoma, DSL-2, was studied. This established transplantable tumor has been maintained in syngeneic rats. Inbred male Lewis rats were pretreated with castration and s.c. implantation of 1.0-mg 17 beta-estradiol (CAS: 50-28-2; estradiol) pellets at 7 weeks of age. Tumor cells were inoculated s.c. on the back of intact male, castrated male, or 17 beta-estradiol-treated castrated male rats. Additional male rats served as non-tumor-bearing controls. There was no difference in the body weight between tumor-bearing and non-tumor-bearing male rats. A distinct difference in the tumor growth was observed in variously conditioned recipients. In castrated male hosts, the serum testosterone levels and the epididymis weights were significantly decreased, and the tumor weights were significantly less as compared to intact control hosts. Additional pretreatment with 17 beta-estradiol caused a markedly slower growth of tumors and increases of the serum 17 beta-estradiol levels and the pituitary weights in castrated male recipients. The remarkable response of tumor growth to castration was also observed in a fast-growing tumor derived from DSL-2. Moreover, close positive relationships between tumor weights and the activities of both serum amylase and lipase were observed. Results showed that the pretreatment with castration alone or in combination with 17 beta-estradiol treatment was able to inhibit the growth of the transplantable tumor. In addition, tumor cells had an ability to produce amylase and lipase, and the amount of enzymic activity was related to the tumor volume. Thus, these data indicate that the transplantable rat pancreatic carcinoma retains physiological function. Our previous study has shown the modulation by sex steroids of azaserine-induced preneoplastic lesions of pancreas in rats. Therefore, androgens and estrogens may play key roles as promoters and inhibitors during the process of pancreatic carcinogenesis.

Amylases↗
PubMed1965

CHLOROPLAST MUTAGENESIS: EFFECT OF N-METHYL-N'NITRO-N-NITROSOGUANIDINE AND SOME OTHER AGENTS ON EUGLENA.

Treatment of normal green Euglena gracilis with N-methyl-N'-nitro-N-nitrosoguanidine results in permanent loss of the ability to form chloroplasts in close to 100 percent of the organisms. The resulting "bleached" strains can be maintained for over 100 generations; no reversion to chloroplast-containing organisms occurs within this time. Alkylating agents, azaserine, mitomycin C, acridines, nitrous acid, hydroxylamine, and gamma-irradiation do not bleach significant proportions of cells even at concentrations sufficient to kill most of the cells. These results may be due partly to differences in the base compositions of nuclear and chloroplast DNA.

Acridines↗
PubMed1965

EFFECT OF HEAT AND PLATING MEDIUM ON SURVIVAL OF ESCHERICHIA COLI AFTER TREATMENT WITH RADIOMIMETIC CHEMICALS.

Zampieri, Antonio (Palo Alto Medical Research Foundation, Palo Alto, Calif.), and Joseph Greenberg. Effect of heat and plating medium on survival of Escherichia coli after treatment with radiomimetic chemicals. J. Bacteriol. 89:931-936. 1965.-Survival of Escherichia coli strain S and its radioresistant mutant R(4) after treatment with mitomycin C, azaserine, nitrogen mustard, 1-methyl-3-nitro-1-nitrosoguanidine, nitrofurazone, and proflavine was studied. With all agents except proflavine, R(4) was more resistant than was S. Survival of strain S was greater on minimal glucose-salts medium than on Penassay (Difco), and greater on the latter than on Tryptone (Difco) agar; survival of S was greater when posttreatment incubation temperature was 45 C than when it was 37 C. Post-treatment plating medium or temperature had no effect on survival of R(4). Visible light did not affect survival of S or R(4). The survival curves of R(4) were exponential; those of S exhibited decreasing sensitivity with time of exposure. With proflavine, photoactivation by visible light was demonstrable, but there was no difference in survival between S and R(4). Survival of either strain was not affected by post-treatment plating medium or incubation temperature.

Acridines↗
PubMed1977

The role of de novo purine synthesis in lymphocyte transformation.

Genetic defects in purine metabolism are associated with severe immunodeficiency. Adenosine deaminase deficiency impairs the function of both B- and T-lymphocytes whereas in purine nucleoside (inosine) phosphorylase deficiency there is more severe impairment of T-lymphocyte functions than of B-lymphocyte functions. The relative unimportance of the salvage pathway catalysed by hypoxanthine-guanine phosphoribosyltransferase is shown by the normal responses of T-lymphocytes from patients with the Lesch-Nyhan syndrome to antigenic and mitogenic stimulation. A mild deficiency of B-lymphocyte function is found in these patients. Agents inhibiting the de novo pathway of purine synthesis, including azaserine, 6-mercaptopurine and azathioprine in low doses, block the responses of normal human lymphocytes to mitogenic stimulation. These observations emphasize the importance of the de novo pathway of purine synthesis in lymphocyte responses to antigenic and mitogenic stimulation. There is considerable heterogeneity in the amount of labelled uridine incorporated into human and rat lymphocytes. This does not appear to reflect only a difference between T- and B-lymphocytes

Adenine Phosphoribosyltransferase↗
PubMed1992

Effects of sandostatin and castration on pancreatic carcinogenesis in rats and hamsters.

The effects of treatment with the somatostatin analogue Sandostatin, separately and in combination with surgical castration, on the development of azaserine-induced lesions in rat pancreas and N-nitrosobis(2-oxopropyl)amine (BOP)-induced lesions in hamster pancreas were investigated. The animals were divided in 4 groups and treated as follows: (a) controls, injected s.c. with saline solution (0.9% NaCl); (b) orchiectomy directly after the last treatment with carcinogen; (c) Sandostatin (SMS 201-995) subcutaneously; (d) orchiectomy followed by treatment with Sandostatin. No significant suppressive effects on plasma EGF or IGF-I concentrations were noted after Sandostatin treatment, but plasma gastrin levels decreased slightly in the rats, not in the hamsters. In rats, Sandostatin treatment enhanced rather than inhibited growth of acidophilic atypical acinar cell nodules. In hamster pancreas, by contrast, Sandostatin inhibited the development of putative pre-neoplastic ductular lesions. There was no interaction between treatment with Sandostatin and surgical castration. It was concluded that Sandostatin, when administered prophylactically, has an inhibitory effect on the growth of putative pre-neoplastic ductular, but not acinar, lesions.

Animals↗
PubMed1995

Effects of aminoglutethimide, alone and in combination with surgical castration, on pancreatic carcinogenesis in rats and hamsters.

The present 12-month study was carried out to investigate the effects of the aromatase inhibitor aminoglutethimide, alone and in combination with orchiectomy, on pancreatic carcinogenesis in azaserine-treated rats and N-nitrosobis(2-oxopropyl)-amine-treated hamsters. Treatment of the animals started 4 months after the last injection with the carcinogen. They were surgically castrated and/or treated with aminoglutethimide. Aminoglutethimide-treated rats developed less pancreatic tumours than did untreated controls. Multiplicity of (pre-)-neoplastic acinar lesions was lower in orchiectomized rats than in intact rats. Inhibition of pancreatic carcinogenesis was most pronounced in rats that were both orchiectomized and treated with aminoglutethimide. These effects were statistically significant after 8 months, but not after 4 months, of treatment. In hamsters, aminoglutethimide showed an enhancing rather than an inhibitory effect on the formation of ductular pancreatic tumours. Castration appeared to have no effect on the development of N-nitrosobis(2-oxopropyl)amine-induced ductular lesions in the pancreas, either alone, or in combination with aminoglutethimide. The present findings indicate that aminoglutethimide, alone and in combination with surgical castration, might be of value for the treatment of pancreatic acinar tumours, whereas the usefulness of aminoglutethimide for treatment of ductular adenocarcinomas of the pancreas is somewhat doubtful.

Aminoglutethimide↗
PubMed1984

Stimulation by glutamine of the formation of N6-hydroxylysine in a cell-free extract from Aerobacter aerogenes 62-1.

Glutamine may serve as an activator and/or regulator of the N6-hydroxylase (E.C. 1.14.99) of Aerobacter aerogenes 62-1. Activation and stabilization of N6-hydroxylase activity was observed both in vivo and in vitro. Growth in a glutamine-supplemented medium resulted in (1) maximum N6-hydroxylase activity at an earlier stage of growth and (2) higher N6-hydroxylase activity and continued aerobactin synthesis into stationary phase. Storage of P2 in the presence of L-glutamine (1 mM) significantly increased the lifetime of the labile N6-hydroxylase activity. Inclusion of L-glutamine in the incubation mixture typically resulted in a 2-3-fold activation of the hydroxylase activity. The stimulatory effect of glutamine was independent of and additive to the enhancement of N6-hydroxylation by the active component(s) in the supernatant, S2 fraction. Glutamic acid-gamma-semihydrazide activated slightly in the absence of glutamine but activation of the system by glutamine was decreased by this compound. Azaserine was shown to be an uncompetitive inhibitor with respect to lysine and this inhibition was not reversed by glutamine.

Azaserine↗
PubMed1979

Purine metabolism in rat skeletal muscle.

1. Rat skeletal muscle can synthesize purine nucleotides de novo. 2. Nucleotide synthesis de novo was inhibited by approximately 90% in the presence of 1 mM azaserine. 3. Purine nucleotides can be synthesized via "salvage" pathways from purine bases and nucleosides. Under the conditions employed incorporation rates were adenosine adenine inosine/hypoxanthine guanosine guanine. 4. Xanthine was not utilized for nucleotide synthesis.

Animals↗
PubMed1986

The effect of the long-term feeding of raw soy flour on the pancreas of the mouse and hamster.

The effects of the long-term feeding of mice and hamsters with raw (RSF) or heated (HSF) soy flours were investigated both in the presence and absence of chemical carcinogens. Mice which had been fed RSF for 18 months had enlarged pancreas but only a relatively low incidence of atypical acinar cell nodules (AACN). Mice on either RSF or HSF were also relatively resistant to the carcinogenic effects of azaserine which is known to produce a high incidence of AACN in rats. Hamsters which had been fed RSF for 15 months did not exhibit pancreatic enlargement and had a very low incidence of pancreatic tumors. Although the incidence of tumors in hamsters which had been injected with N-nitrosobis (2-oxopropyl)amine and maintained on HSF was very high (88%), those on RSF had a tumor incidence of less than 10%. Thus, there appears to be a marked difference in the response of the pancreas in different species of animals to the long-term effects of feeding RSF. This should be taken into consideration in evaluating the potential carcinogenicity of the trypsin inhibitors.

Animals↗
PubMed1986

Enhancement of pancreatic carcinogenesis by raw soy protein isolate: quantitative rat model and nutritional considerations.

Foods containing soybean products have been shown to modify the biochemical and physiological status of the pancreas of several species of experimental animals. Recently, these products have been implicated as a factor in the causation of pancreatic neoplasms. Extensive experimental studies into the possible mechanisms need to be undertaken. Experimental details of a rat/azaserine model for the study of pancreatic carcinogenesis are reviewed. Emphasis is given to the quantitative components of this model and the adaptation of this model to the two-stage (initiation-promotion) concept of carcinogenesis. Particular attention is devoted to considerations of the experimental diets. Application of these concepts to the study of the postinitiational effects of raw and heated soybean protein isolate with and without the addition of high levels of unsaturated fat were undertaken. The results indicate that raw soybean isolate enhanced the growth of azaserine-induced pancreatic foci; whereas, a high level of unsaturated fat had a minimal effect. The effects of the soybean isolate were abolished by heat treatments, but the effects of the unsaturated fat would not be expected to be abolished by similar treatment with heat.

Animals↗
PubMed1975

Purine mutants of mammalian cell lines. II. Identification of a phosphoribosylpyrophosphate amidotransferase-deficient mutant of Chinese hamster lung cells.

A class of purine auxotrophs blocked early in the purine biosynthetic pathway was examined. The inability of these mutants to accumulate formylglycinamide ribotide (FGAR) in the presence of azaserine suggested that one or more of the first three enzymes of the pathway were either missing or defective. By direct enzyme assay, phosphoribosylpyrophosphate (PRPP) amidotransferase (E.C. 2.4.2.14) was found to be absent in extracts of mutant cells. Thus these cells were unable to convert PRPP to phosphoribosylamine (PRA). By reacting ribose 5-phosphate with ammonium ions, PRA was generated nonenzymatically in the incubation mixture, thus enabling us to test for the presence of the two enzymes required to convert PRA to FGAR. It was demonstrated that sufficient amounts of these enzymes, phosphoribosylglycineamide synthetase (E.C. 6.3.1.3) and phosphoribosylglycineamide formyltransferase (E.C. 2.1.2.2), were present in mutant extracts to allow synthesis of FGAR to occur once PRA was so provided.

Adenine↗
PubMed1991

Affinity of antineoplastic amino acid drugs for the large neutral amino acid transporter of the blood-brain barrier.

The relative affinity of six anticancer amino acid drugs for the neutral amino acid carrier of the blood-brain barrier was examined in rats using an in situ brain perfusion technique. Affinity was evaluated from the concentration-dependent inhibition of L-[14C]-leucine uptake into rat brain during perfusion at tracer leucine concentrations and in the absence of competing amino acids. Of the six drugs tested, five, including melphalan, azaserine, acivicin, 6-diazo-5-oxo-L-norleucine, and buthionine sulfoximine, exhibited only low affinity for the carrier, displaying transport inhibition constants (Ki, concentrations producing 50% inhibition) ranging from 0.09 to 4.7 mM. However, one agent - D,L-2-amino-7-bis[(2-chloroethyl)amino]- 1,2,3,4-tetrahydro-2-naphthoic acid (D,L-NAM) - demonstrated remarkably high affinity for the carrier, showing a Ki value of approximately 0.2 microM. The relative affinity (1/Ki) of D,L-NAM was greater than 100-fold that of the other drugs and greater than 10-fold that of any compound previously tested. As the blood-brain barrier penetrability of most endogenous neutral amino acids is related to their carrier affinity, the results suggest that D,L-NAM may be a promising agent which may show enhanced uptake and distribution to brain tumors.

2-Naphthylamine↗
PubMed1985

Isolation and characterization of a mutant Chinese hamster cell line resistant to the glutamine analog 6-diazo-5-oxo-L-norleucine.

A mutant cell line, called don801, was isolated from a wild-type population of V79.5 Chinese hamster cells by its ability to grow in the presence of the glutamine analog 6-diazo-5-oxo-L-norleucine (DON), which is toxic for V79.5 cells. The don801 cells were found not to be cross-resistant to another glutamine analog, O-diazoacetyl-L-serine (azaserine, AS). It was shown that guanine but neither hypoxanthine nor adenine protected V79.5 cells from the toxic effects of DON, while hypoxanthine and adenine, but not guanine protected them against AS toxicity. Exposure of wild-type cells to DON was shown to result in a specific reduction of intracellular GTP pools, while in the mutant cells there was no effect on GTP levels. These results strongly suggested that DON was specifically inhibiting guanylate synthetase (GMP synthetase;xanthosine-5'-phosphate: L-glutamine amidoligase, EC 6.3.5.2) in V79.5 cells and that the enzyme in don801 cells was resistant to inhibition. In vitro assays of GMP synthetase activities from V79.5 and don801 cells confirmed this hypothesis. The mutant phenotype was also found to be dominant in intraspecific cell hybrids.

Animals↗
PubMed1989

Modulation of putative preneoplastic foci in exocrine pancreas of rats and hamsters. Interaction of dietary fat and coffee.

The effects of coffee and dietary fat (alone and in combination) on the development of preneoplastic lesions in exocrine pancreas were investigated in rats and hamsters, treated with azaserine or N-nitrosobis(2-oxopropyl)amine, respectively. The animals were given the respective diets (5% or 25% corn oil) and coffee (instead of drinking water) within one week after the treatment with carcinogen. At four months postinitiation, the pancreata were quantitatively examined for the number and size of preneoplastic foci. In rats, coffee alone inhibited growth of acidophilic foci and, moreover, slightly inhibited the positive modulating effect of fat on growth of these foci, pointing to a negative rather than a positive interaction between these two life-style factors. In hamsters, coffee alone enhanced growth of cystic foci, whereas fat alone enhanced growth of ductular foci. An interaction between fat and coffee on pancreatic carcinogenesis in hamsters could not be demonstrated.

Animals↗