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At least 19 recordsLinked to original sources
PubMed1991

Medicinal azides. Part 8. The in vitro metabolism of p-substituted phenyl azides.

1. A series of p-substituted aromatic azides was synthesized and their metabolism investigated in suspensions of mouse liver microsomes and mouse hepatocytes. Metabolite analysis was performed by h.p.l.c. 2. On incubation with microsomes under anaerobic conditions p-nitro, p-cyano- and p-chlorophenyl azide afforded metabolites which co-chromatographed with the respective aromatic amines. The rate at which p-nitrophenyl azide was metabolically reduced was approximately 20-fold that observed for p-cyano- and p-chlorophenyl azide. 3. Phenyl azide, p-methoxyphenyl azide and the aliphatic congener, phenethyl azide, did not furnish detectable amounts of metabolites on incubation with microsomes under anaerobic conditions. When phenyl azide and p-methoxyphenyl azide were incubated with hepatocytes or microsomes under aerobic conditions the resulting chromatograms furnished peaks which co-eluted with authentic p-hydroxyphenyl azide. 4. The microsomal reduction of p-nitrophenyl azide was dependent upon the presence of viable microsomes and NADPH, and on the absence of oxygen above the incubation medium.

Aerobiosis↗
PubMed1989

Sodium azide mutagenesis in mammals: inability of mammalian cells to convert azide to a mutagenic intermediate.

Sodium azide is unique among mutagens. It is highly mutagenic in many plant and bacterial species but marginally mutagenic in mammalian cells. A possible explanation for this difference in mutagenic efficiency may lie in the inability of mammalian cells to convert azide to the putative ultimate mutagen. Normal human fibroblasts and Chinese hamster cells or cell-free extracts from these cell lines were treated with azide and the sonicates tested for mutagenicity in Salmonella strain TA1530. The data suggest that neither cell line was capable of converting azide to a mutagenic intermediate. In addition, both cell lines expressed the enzyme O-acetylserine(thio)-lyase which is responsible for the conversion of azide to azidoalanine, the putative mutagenic intermediate. Although mammalian cells possess the enzyme responsible for the conversion of azide to azidoalanine, they appear incapable of converting azide into a mutagenic intermediate in appreciable quantities. Further, the data support the conclusion that azide may be further modified in mammalian cells to an intermediate that is not genotoxic.

Animals↗
PubMed1991

Efficient and selective photoaffinity labeling of the estrogen receptor using two nonsteroidal ligands that embody aryl azide or tetrafluoroaryl azide photoreactive functions.

3-(4-Azido-2,3,5,6-tetrafluorobenzoyl)-6-hydroxy-2-(4- hydroxyphenyl)benzo[b]thiophene 1 (tetrafluoroaryl azide, TFAA) and its protio analogue 3-(4-azidobenzoyl)-6- hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophene 2 (protioaryl azide, PAA), photoaffinity labeling (PAL) reagents for the estrogen receptor (ER), have been prepared in high specific activity tritium-labeled form (19 Ci/mmol) and shown to undergo selective and efficient photocovalent attachment to ER from rat uterus. Both azides 1 and 2 demonstrate high binding affinity for ER as determined by both a competitive binding assay (relative binding affinities: estradiol = 100; TFAA = 9.3; PAA = 66) and a direct binding assay (Kd: estradiol = 0.24 nM; TFAA = 2.64 nM; PAA = 0.37 nM). When unlabeled TFAA and PAA are irradiated at greater than 315 nm, they demonstrate site-specific photoinactivation of ER that reaches 43% and 55%, respectively, by 30 min. Specific photocovalent attachment to ER can be effected by irradiation of the tritium-labeled azides; the covalent attachment efficiency is good (1 = 20-30%, 2 = ca. 25%) and the selectivity of ER labeling is high. Characterization of the photolabeled proteins by SDS-polyacrylamide gel electrophoresis shows specific labeling of a major component at Mr 60,000 and a minor species at Mr 46,000, the same two species that are labeled by [3H]tamoxifen aziridine, a well-characterized affinity label for ER. The ER-specific antibodies H222Sp gamma and D547Sp gamma show a clean precipitation of only these two species. In the MCF-7 human breast cancer cell line, PAA is a full estrogen agonist in terms of stimulation of cell proliferation and induction of progesterone receptor. These two azides provide the first system in which the photocovalent attachment efficiency of an aryl azide can be compared to its tetrafluorosubstituted aryl azide analogue in a complex biological receptor system. Azides 1 and 2 are the most efficient and selective PAL reagents prepared to date for ER, and they should be useful in further studies of the hormone-binding domain of this protein.

Affinity Labels↗
PubMed1987

B-cells purified using azide give different responses in vitro to B-cells purified without azide.

Some established techniques for B-cell enrichment include azide in the media. Here, B-cells were enriched using a technique which transiently exposed the cells of 15 mM sodium azide. After 3-4 days in culture, the precursor frequency of autoantibody-secreting cells in this population was 0.113%. In contrast, when B-cells were enriched using a technique which eliminated their exposure to sodium azide, the number of autoantibody-secreting precursor cells detected in cultures was increased up to 20-fold. Therefore, it is concluded that transient exposure to azide affects functional activities of B-cells in vitro.

Animals↗
PubMed1990

Azide-resistant mutants of Escherichia coli alter the SecA protein, an azide-sensitive component of the protein export machinery.

Escherichia coli azi mutants, whose growth is resistant to millimolar concentrations of sodium azide, were among the earliest E. coli mutants isolated. Genetic complementation, mapping, and DNA sequence analysis now show that these mutations are alleles of the secA gene, which is essential for protein export across the E. coli plasma membrane. We have found that sodium azide is an extremely rapid and potent inhibitor of protein export in vivo and that azi mutants are more resistant to such inhibition. Furthermore, SecA-dependent in vitro protein translocation and ATPase activities are inhibited by sodium azide, and SecA protein prepared from an azi mutant strain is more resistant to such inhibition. These studies point to the utility of specific inhibitors of protein export, such as sodium azide, in facilitating the dissection of the function of individual components of the protein export machinery.

Adenosine Triphosphatases↗
PubMed1989

Differential metabolism of sodium azide in maize callus and germinating embryos.

Sodium azide is a potent mutagen of maize (Zea mays L.) kernels that may have potential as a point mutagen for inducing biochemical mutations in maize tissue cultures. Azide mutagenicity was evaluated in friable, embryogenic maize callus and a nonregenerable maize suspension culture by determining the number of resistant variant cell lines able to grow on media containing inhibitory concentrations of lysine plus threonine (LT). The number of LT-resistant variants selected from either culture type did not increase in response to azide treatment. In addition, there was no increase in somatic mutations in more than 100 plants regenerated from azide treated LT-resistant lines. The levels of mutagenic metabolite of azide (presumably azidoalanine), were determined by bioassay in the two azide-treated maize callus types and compared to levels of mutagenic metabolite in embryos isolated from azide-treated kernels. The two types of maize tissue cultures and isolated embryos contained similar levels of mutagenic metabolite 4 h after azide treatment indicating similar uptake and conversion of azide to mutagenic metabolite in the three tissues. Mutagenic metabolite in azide-treated embryos did not significantly decrease after 40 h. However, mutagenic metabolite levels in both azide-treated tissue cultures decreased to near background levels within 20 h providing evidence for rapid metabolism of the azide mutagenic metabolite. The lack of evidence for azide mutagenicity in maize callus and its known potent mutagenicity in kernels appears to be associated with specific differences in azide metabolism between callus tissues and kernel embryos.

Azides↗
PubMed1976

Effect of excision repair on azide-induced mutagenesis.

Azide mutagenesis was investigated in Salmonella typhimurium and Escherichia coli. Azide was highly effective in inducing his+ revertants in excision-repair deficient (uvrB) derivatives of S. typhimurium hisG46 and in inducing high frequencies of 5-fluorouracil resistant mutants in excision-repair deficient (uvrA) derivatives of E. coli B/r WP2. In excision-repair plus strains, azide was only a marginal or ineffective mutagen, demonstrating that the bacterial excision-repair system could repair nearly all azide-induced damage. This observation suggests that the initial azide-induced lesion causes a major DNA helix distortion recognizable by the excision-repair endonucleases. The presence of recombination deficient (recB or recC) genes in combination with uvrA increased E. coli sensitivity to azide killing, but depressed azide mutagenicity. These results are similar to those reported for UV-induced mutagenesis with the E. coli strains and suggest that post-replication repair might be the error-prone step in the repair process. Azide mutagenesis specificity is, however, unique and different from UV, as demonstrated by inability of azide to revert the ochre try locus in E. coli WP2s. These results show that the initial azide-induced DNA damage is highly specific but different from UV-induced DNA damage. Metabolic inhibitors, similar in action to azide, did not induce mutations in S. typhimurium strain TA1530, a strain highly susceptible to azide mutagenesis, thus ruling out the possibility that azide mutagenesis was due to peroxide accumulation. A mechanism based on in vivo activation of azide to the actual mutagen is proposed.

Azides↗
PubMed1989

Azide as a probe of co-operative interactions in the mitochondrial F1-ATPase.

(1) The hydrolytic activity of the isolated mitochondrial ATPase (F1) is strongly inhibited by azide. However, at very low ATP concentration (1 microM or less), no inhibition by azide is observed. (2) The azide-insensitive ATPase activity represents a high-affinity, low-capacity mode of turnover of F1. This is identified with the low Km, low Vmax component seen in steady-state kinetic studies in the absence of azide. (3) The azide-insensitive ATPase activity shows simple Michaelis-Menten kinetics, with Km = 3.2 microM, and Vmax = 1.1 mumol/min per mg (6 s-1). It is unaffected by anions such as sulphite, or by increasing pH in the range 7 to 8, both of which stimulate the maximal activity of F1. (4) Both the azide-insensitive and azide-sensitive components of F1-ATPase activity are equally inhibited by labelling the enzyme with 7-chloro-4-nitrobenzofurazan, by binding the natural inhibitor protein, or by cold denaturation of the enzyme. (5) It is concluded that azide-insensitive ATP hydrolysis represents catalysis by F1 involving a single catalytic site, and that azide acts by abolishing intersubunit cooperativity between the three catalytic sites of F1. Azide-sensitivity is thus a useful probe for events which affect the active site of F1 directly.

Adenosine Triphosphate↗
PubMed1989

A defective proton pump, point-mutated bacteriorhodopsin Asp96----Asn is fully reactivated by azide.

Addition of azide fully restored the proton pump activity of defective bacteriorhodopsin (BR) mutant protein Asp96----Asn. The decay time of M of BR Asp96----Asn, the longest living intermediate, was decreased from 500 ms at pH 7.0 to approximately 1 ms under conditions of saturating azide concentrations. This decay was faster than the decay of M in the wild-type, where no such azide effect was detectable. Stationary photocurrents, measured with purple membranes immobilized and oriented in a polyacrylamide gel, increased upon addition of azide up to the level of the wild-type. Different small anions of weak acids restored the pump activity with decreasing affinity in the order: cyanate greater than azide greater than nitrite greater than formiate greater than acetate. The activation energy of the M decay in the mutant was higher in the presence (48 kJ/mol) than in the absence (27 kJ/mol) of 100 mM azide even though the absolute rate was dramatically increased by azide. This effect of azide is due to the substitution of a carboxamido group for a carboxylic group at position 96 which removes the internal proton donor and causes an increase in the entropy change of activation for proton transfer which is reversed by azide.

Anions↗
PubMed1974

Inhibition of DNA synthesis and cell division in Salmonella typhimurium by azide.

Evidence has been obtained that sodium azide is an inhibitor of cell division in wild-type and aziA strains of Salmonella typhimurium. The bacteria grown in media containing sodium azide and glucose formed long filaments. It has been found that sodium azide had a stronger inhibitory effect on DNA synthesis than on cell mass increase. When filaments produced by azide action were transferred to azide-free medium very rapid increase in DNA content was observed during the first 45 min. After this time, when relative DNA content was increased the rate of DNA synthesis was reduced and cell divisions reappeared. Inhibitory effect of azide on DNA biosynthesis in vitro was observed with toluenized cells of S typhimurium. Only ATP-dependent radioactive dTMP incorporation into DNA was affected by sodium azide. It had no effect on the incorporation in the absence of ATP. Mutant aziC was isolated in S. typhimurium by scoring for clones with normal cell division in the presence of sodium azide. Azide had much less effect on DNA biosynthesis in vivo and in vitro in aziC cells as compared with isogenic controls.

Azides↗
PubMed1989

31P nuclear magnetic resonance study of the effect of azide on xylose fermentation by Candida tropicalis.

Maximal ethanol production by Candida tropicalis grown on xylose was obtained at an oxygen transfer rate of 5 to 7 mmol/liter per h. Addition of 0.2 mM azide increased the ethanol yield by a factor of 3 to 4, based on the cell mass produced, and decreased the formation of the by-product xylitol by 80%. In the presence of azide, ethanol was reassimilated before the carbon source was depleted. At all oxygenation levels studied, azide caused 25 to 60% of the carbon to be lost, most probably as carbon dioxide. Identical spectra were obtained with 31P nuclear magnetic resonance spectroscopy performed on extracts of C. tropicalis grown on xylose in the absence and presence of azide. Azide lowered the levels of sugar phosphates. Enzymatic analysis showed extremely low levels of fructose 1,6-diphosphate compared with the levels obtained in the absence of azide, while the level of malate, a citric acid cycle intermediate, was not influenced by azide. 31P nuclear magnetic resonance spectroscopy performed on xylose-grown whole cells of C. tropicalis showed that azide lowered the intracellular pH, inhibited the uptake of external Pi, and decreased the buildup of polyphosphate in relation to results with untreated cells. Similar results were obtained with the uncoupler of oxidative phosphorylation carbonyl cyanide m-chlorophenylhydrazone (CCCP), except that CCCP treatment led to extremely high levels of internal Pi. The dual effect of azide as a respiratory inhibitor and as an uncoupler is discussed with respect to the metabolism and product formation in xylose-assimilating C. tropicalis.

Azides↗
PubMed1986

Sodium azide is less suitable as a positive control of drug-induced lethality for in vitro clonogenic assays.

Sodium azide (6 mg/ml) was used as a positive control for drug-induced lethality in an in vitro clonogenic assay. Petri dishes containing control and sodium azide treated cultures of WiDr cells were placed together in a large Petri dish and incubated at 37 degrees C in an atmosphere of 10% CO2 in air. No growth was observed. Control cells formed colonies only when the dishes were separated from the sodium azide dishes. Using a microtiter plate the toxic effect was inversely related to the distance of the test cultures from the sodium azide treated cultures. These results suggested the formation of a toxic gas or vapour from sodium azide under cell culture conditions, probably an azide. Chemical analysis was based on characteristic reactions, such as the production of a precipitate with silver ions or formation of a red-coloured complex with ferric salts. On a microtiter plate, a gradient of the expected precipitate or red colour was observed, the highest amounts adjacent to the wells containing sodium azide. These results show that sodium azide acts as a positive control of drug-induced lethality for in vitro clonogenic assays. However, the formation of a highly toxic vapour, most likely hydrazaic acid, makes it a less suitable standard.

Azides↗
PubMed1991

Acute neurotoxicity of sodium azide and nitric oxide.

Sodium azide is a chemical of rapidly growing commercial importance with a high acute toxicity and an unknown mechanism of action. Although it has some chemical properties and biological effects in common with cyanide, its lethality does not appear to be due to inhibition of cytochrome oxidase. Unlike cyanide it is a potent vasodilator and inhibitor of platelet aggregation presumably by virtue of its conversion to nitric oxide in vivo and in isolated preparations of blood vessels and thrombocytes. It is not clear whether the high toxicity of azide is due to nitric oxide or to the parent anion. Of a number of possible azide antagonists tested in intact mice only phenobarbital in both anesthetic and subanesthetic doses afforded statistically significant protection against death. Diazepam, phenytoin, and an anesthetic dose of a ketamine/xylazine combination had no effect. Major motor seizures are sometimes seen in human azide poisoning, and these are a regular feature of azide poisoning in laboratory rodents. Solutions of nitric oxide given systemically to mice produced no signs of toxicity, but doses 1,000-fold lower placed in the cerebroventricular system of rats produced brief but violent tonic convulsive episodes. A dose of 0.61 mmol/kg azide as given systemically regularly produced convulsions whereas a dose of 6 mumol/kg given icv produced seizures in rats. The icv convulsive dose of azide was 50-fold larger than the icv dose of nitric oxide. These results suggest that azide lethality is due to enhanced excitatory transmission in the central nervous system perhaps after its conversion to nitric oxide.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1977

Effects of sodium azide on photosystem II of Chlorella pyrenoidosa.

The action of sodium azide on the electron transport chain was investigated by means of oxygen evolution, fluorescence and luminescence measurements. (1) The damping of the oxygen oscillations is progressively reduced with increasing azide concentration in the range of 10(-5) - 10(-1) M. (2) The rate of the dark decay of the S2 and S3 states is considerably slowed. The degree of slowing is dependent on concentration. (3) Luminescence is inhibited by azide both in the presence and absence of 3-(3,4-dichlorophenyl)-1,1-dimethylurea (DCMU). (4) The fluorescence induction curve in strong light is modified in the presence of azide and its shape depends on azide concentration and on incubation time. (5) At a given time after a saturating flash, the fluorescence yield in the presence of azide is much higher than that of the control. It seems to be due to a general fluorescence increase rather than to a slower Q- reduction. (6) We tentatively propose an accelerated reduction of the primary donor P+ in state S2 and S3, by the intermediate donor Z in the presence of azide. Additionally, we have to assume that in the S2 and S3 states, some centers are blocked in an inactive low fluorescent form and that azide decreases their concentration.

Azides↗