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PubMed1988

Acridine orange as a screen for organisms in clinical specimens and comparison with gram's stain.

We compared the result of acridine orange and Gram's stains with the results of culture for 202 wound swabs and 188 fluid specimens. Cerebrospinal fluid was excluded from the study. Acridine orange was more sensitive and less specific than Gram's stain compared with findings that have been previously reported. A difference in the sensitivity was observed between the two stains and between the types of specimens examined themselves. The sensitivity of acridine orange and Gram's stains was 83% and 49% for swabs and 66% and 45% for fluids, respectively. The negative predictive values for acridine orange and Gram's stains were 60% and 40% for swabs and 84% and 81% for fluids, respectively. Overall, the sensitivity for acridine orange and Gram's stains was 75% and 64% with negative predictive values of 75% and 63%, respectively; specificity was 75% (acridine orange) and 97% (Gram's stain) and did not differ significantly between the two specimen types. Acridine orange was cleaner, faster, easier to perform and read, and less costly than Gram's stain for screening purposes. Slides that were positive by acridine orange staining should be stained with Gram's stain for specificity and for the Gram's-stain reaction report. Acridine orange is recommended for screening smears, with positive results confirmed by Gram's stain.

Abscess↗
PubMed2004

Scandium ion-promoted photoinduced electron transfer from electron donors to acridine and pyrene. Essential role of scandium ion in photocatalytic oxygenation of hexamethylbenzene.

Photoinduced electron transfer from a variety of electron donors including alkylbenzenes to the singlet excited state of acridine and pyrene is accelerated significantly by the presence of scandium triflate [Sc(OTf)(3)] in acetonitrile, whereas no photoinduced electron transfer from alkylbenzenes to the singlet excited state of acridine or pyrene takes place in the absence of Sc(OTf)(3). The rate constants of the Sc(OTf)(3)-promoted photoinduced electron-transfer reactions (k(et)) of acridine to afford the complex between acridine radical anion and Sc(OTf)(3) remain constant under the conditions such that all the acridine molecules form the complex with Sc(OTf)(3). In contrast to the case of acridine, the k(et) value of the Sc(OTf)(3)-promoted photoinduced electron transfer of pyrene increases with an increase in concentration of Sc(OTf)(3) to exhibit first-order dependence on [Sc(OTf)(3)] at low concentrations, changing to second-order dependence at high concentrations. The first-order and second-order dependence of k(et) on [Sc(OTf)(3)] is ascribed to the 1:1 and 1:2 complexes formation between pyrene radical anion and Sc(OTf)(3). The positive shifts of the one-electron redox potentials for the couple between the singlet excited state and the ground-state radical anion of acridine and pyrene in the presence of Sc(OTf)(3) as compared to those in the absence of Sc(OTf)(3) have been determined by adapting the free energy relationship for the photoinduced electron-transfer reactions. The Sc(OTf)(3)-promoted photoinduced electron transfer from hexamethylbenzene to the singlet excited state of acridine or pyrene leads to efficient oxygenation of hexamethylbenzene to produce pentamethylbenzyl alcohol which is further oxygenated under prolonged photoirradiation of an O(2)-saturated acetonitrile solution of hexamethylbenzene in the presence of acridine or pyrene which acts as a photocatalyst together with Sc(OTf)(3). The photocatalytic oxygenation mechanism has been proposed based on the studies on the quantum yields, the fluorescence quenching, and direct detection of the reaction intermediates by ESR and laser flash photolysis.

Journal Article↗
PubMedDate not supplied

Acridine-induced subcellular and functional changes in isolated human hepatocytes in vitro.

Acridines are nucleic acid intercalating compounds with properties relating to the complexity of their structure. Tetrahydroaminoacridine (tacrine, Cognex), a simple acridine, is a reversible inhibitor of cholinesterase activity available for the symptomatic treatment of Alzheimer's disease. Tacrine therapy causes sporadic elevations of aminotransferases in humans, and tacrine alters protein synthesis and ribosomal structure under short-term in vitro exposures in isolated hepatocytes from humans and other species. There is no clear relationship between transaminase elevation and liver damage in humans, and prolonged drug exposure to animals does not result in hepatic insult. Subcellular alterations have been described in isolated human and rodent hepatocytes, including degranulation and vesiculation of the endoplasmic reticulum (ER), aggregation of electron-dense structures within the ER, altered nuclei and nucleoli and detrimental structural and functional effects to mitochondria. Whether these changes in hepatocyte morphology and function are unique to tacrine or not is unknown, as human hepatocytes exposed to more complex acridines have not been characterized. In this study, we extended the results of in vitro studies with tacrine to acridine orange, 9-aminoacridine, quinacrine and proflavin. In primary human hepatocytes, these compounds caused a similar reduction of mitochondrial membrane potential with parallel ultrastructural changes. The 1-hydroxy and 7-hydroxy tacrine metabolites, acridine hydrochloride and acridine 9-carboxylic acid, and the non-acridine cholinesterase inhibitor eserine, did not induce characteristic subcellular ER changes but damaged mitochondria structure, reduced mitochondrial membrane potential and were cytotoxic. These data indicate that the tacrine-like subcellular changes in hepatocytes are reproducible with other acridines and cause mitochondrial dysfunction in human hepatocytes.

Acridines↗
PubMed1979

Photodynamic effects of dyes on bacteria. II. Genetic effects of broad-spectrum visible light in the presence of acridine dyes and methylene blue in chemostat cultures of Escherichia coli.

Photodynamic mutagenesis was studied in chemostat cultures of Escherichia coli B/r (TlR trp) exposed to one of six different acridine dyes or methylene blue. Mutation to phage T5 resistance was induced with a broad-spectrum fluorescent-light source. All of the agents tested were photomutagenic; acridine yellow was the most efficient sensitizer and quinacrine was the least efficient. Quinacrine also was moderately mutagenic in the dark, in contrast to the other agents tested, which were not significantly mutagenic in the dark at the low concentrations tested for photomutagenesis. The mutation rate with acridine orange was directly proportional to both fluence rate and dye concentration over the ranges tested. Photomutation rates with acridine orange, proflavine and methylene blue were independent of growth rate of the chemostat cultures. These results are consistent with photomutagenesis occurring as the result of photochemical damage to DNA-dye complexes, independent of cell expression was approximately 2.5 generations for each of the photomutagens tested. This short expression delay supports an earlier segregational model for expression of phage resistance. The following results suggest that photodynamic mutagenesis is due mainly to intercalated dye molecules: (1) both acridine and 9-aminoacridine are photodynamic mutagens; (2) acridine inhibits photomutagenesis with acridine orange; and (3) neither putrescine or spermine, which bind to DNA without intercalating, inhibited photomutagenesis by acridine orange or proflavine.

Acridines↗
PubMed1991

The genetic toxicology of acridines.

Acridine and its derivatives are planar polycyclic aromatic molecules which bind tightly but reversibly to DNA by intercalation, but do not usually covalently interact with it. Acridines have a broad spectrum of biological activities, and a number of derivatives are widely used as antibacterial, antiprotozoal and anticancer drugs. Simple acridines show activity as frameshift mutagens, especially in bacteriophage and bacterial assays, by virtue of their intercalative DNA-binding ability. Acridines bearing additional fused aromatic rings (benzacridines) show little activity as frameshift mutagens, but interact covalently with DNA following metabolic activation (forming predominantly base-pair substitution mutations). Compounds where the acridine acts as a carrier to target alkylating agents to DNA (e.g. the ICR compounds) cause predominantly frameshift as well as base-pair substitution mutations in both bacterial and mammalian cells. Nitroacridines may act as simple acridines or (following nitro group reduction) as alkylating agents, depending upon the position of the nitro group. Acridine-based topoisomerase II inhibitors, although frameshift mutagens in bacteria and bacteriophage systems, are primarily chromosomal mutagens in mammalian cells. These mutagenic activities are important, since the compounds have considerable potential as clinical antitumour drugs. Although evidence suggests that simple acridines are not animal or human carcinogens, a number of the derived compounds are highly active in this capacity.

Acridines↗
PubMed2003

Use of diamide-acridine orange fluorescence staining to detect aberrant protamination of human-ejaculated sperm nuclei.

OBJECTIVE: To investigate the influence of human sperm nuclear chromatin on fertilization. DESIGN: Prospective study. SETTING: Assisted reproductive technology unit at a university teaching hospital. PATIENT(S): Fifty men starting an IVF-ET program. INTERVENTION(S): Epifluorescent microscopic observation of human-ejaculated sperm nuclei stained with diamide-acridine orange. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) analysis of extracted sperm nucleoproteins. MAIN OUTCOME MEASURE(S): Usefulness of diamide-acridine orange in analysis of human sperm nuclear chromatin and fertilization ability. RESULT(S): There was no correlation between the semen parameters and the diamide-acridine orange observation. A positive correlation was observed between the fertilization rate after conventional IVF and the green-type increase ratio (percentage of green-pattern sperm after diamide-acridine orange staining/percentage of green-pattern sperm after acridine orange staining). Furthermore, it was suggested by SDS-PAGE that structural differences were noticed between the fertile men and the men with sperm immaturity diagnosed after diamide-acridine orange staining. CONCLUSION(S): Diamide-acridine orange staining was a more precise method for detecting chromatin abnormalities in human-ejaculated sperm and evaluating fertilization ability than acridine orange staining alone. This method can be used as a diagnostic tool to assess the fertilization ability of human-ejaculated spermatozoa before IVF procedures.

Acridine Orange↗
PubMed1976

DNA polyintercalating drugs. Proton magnetic resonance studies of a new acridine dimer. Conformations and interactions with mono- and dinucleotides.

The conformation in aqueous solution of one acridine dimer which is able to bisintercalate in DNA (1, 14-bis(5-methoxy-6-chloro-9-acridinyl)-1,5,10,14-tetraazatetradecane tetrahydrochloride) (AcDi) and its interactions with mono- and dinucleotides have been investigated by fast Fourier transform proton magnetic resonance spectroscopy. Variations in chemical shifts of the most distingusihable protons of the acridine dimer with temperature bring evidence of a folded in equilibrium unfolded fast conformational equilibrium in the temperature range of 4-85 degrees C. Equilibrium parameters were estimated. The folded conformation has been deduced from iso-shielding curves of the acridine ring. In the complex between AcDi and 3'- or 5"AMP, and adenine ring is intercalated between the two acridine rings to give a sandwich-like complex. Studies of the interaction with adenylyl(3' leads to 5') adenosine (ApA) show two different complexes in equilibrium with the 3' or 5' moiety of ApA intercalated in the acridine dimer. These conclusions are derived from comparative studies with 2-methoxy-6-chloro-9-(3-dimethylaminopropylamino)acridine dihydrochloride which is the corresponding acridine monomer-(AcMo). In that case the self-association constant was determined. A model of the AcMo-5'-AMP complex was deduced from the analysis of the chemical shifts of the adenine protons. In this model, the N10+-D bond of the acridine points toward the negatively charged phosphate of the nucleotide.

Acridines↗
PubMed2002

UV absorbance dependent toxicity of acridine to the marine diatom Phaeodactylum tricornutum.

The present study seeks quantitative measures for photoenhanced toxicity under natural light regimes by comparing the effects of an aromatic compound under natural and laboratory light. To this purpose, the influence of light irradiance and spectral composition on the extent of photoenhanced toxicity of acridine, a three-ringed azaarene, to the marine diatom Phaeodactylum tricornutum was analyzed. Under laboratory light containing ultraviolet radiation (UV), the 72-h EC50 growth value for acridine was 1.55 microM. Under natural light, a 72-h EC50 value for acridine below the lowest test concentration (0.44 microM) was observed. Under both laboratory and natural light, the toxicity of acridine was equally enhanced by total UV (UV-A and UV-B) and UV-A radiation, while in the absence of UV no enhancement of toxicity was observed. Hence, the UV-A region of light was dominant in the photoenhanced toxicity of acridine to P. tricornutum, in accordance with its absorption spectrum in the UV-A region. Therefore, the total amount of UV radiation absorbed by aqueous acridine was calculated for each separate treatment. The amount of UV absorbed by acridine effectively described the effect of acridine on the growth of P. tricornutum in a dose-response-dependent manner. It is concluded that photoenhanced toxicity of aromatic compounds expressed as a function of the actually absorbed UV may circumvent some of the variability between studies using different concentrations of the phototoxic compounds and light sources. The UV quantity absorbed by these compounds allows a comparison with the absorption characteristics of natural waters and, thus, is a key parameter to determine the role of photoenhanced toxicity in water.

Acridines↗
PubMedDate not supplied

Pharmacodynamic behavior of [14C]acridine in the cricket Acheta domesticus (L.).

Cuticular and gastrointestinal penetration, in vivo metabolism, and excretion of [14C]acridine were investigated in the nymphal cricket Acheta domesticus (L.) to find a pharmacodynamic basis for this insect's differential susceptibility to acridine at different life stages. Topically applied [14C]acridine readily penetrated the cuticular exoskeleton of nymphs (half-time of penetration, 48 min). Radiolabeled compounds appeared in the hemolymph within 0.5 h after ingestion of [14C]acridine and continued to move across the gut wall for 7.5 h. The biological half-time was 18 h and the rate constant for elimination was 0.039 h-1 after ingestion. Within 5 d after dosing, 97% of the dose was excreted. Several metabolites were present in the feces of nymphs fed [14C]acridine, and less than 13% of the extractable radioactivity was parent compound. The cuticle and the gastrointestinal tract proved to be ineffective barriers to acridine entry in A, domesticus. However, the ability to readily metabolize and excrete acridine probably contributes to the higher acridine tolerance observed in the nymphs and adults than in the eggs, which are susceptible to toxic effects.

Acridines↗
PubMed1983

Metabolism of 7-methylbenz[c]acridine: comparison of rat liver and lung microsomal preparations and identification of some minor metabolites.

The metabolism of the carcinogenic polycyclic aza-aromatic compound, 7-methylbenz[c]acridine, has been studied in lung and liver microsomal preparations obtained from control and induced rats. Minor metabolites not previously identified included, trans-10,11-dihydro-10,11-dihydroxy-7-methylbenz[c]acridine, trans-1,2-dihydro-1,2-dihydroxy-7-methylbenz[c]acridine, 7-methylbenz[c]acridine-5,6-oxide and 7-hydroxymethylbenz[c]acridine-5,6-oxide. Metabolite profiles from liver microsomes showed 7-hydroxymethylbenz[c]acridine, trans-8,9-diydro-8,9-dihydroxy-7-methylbenz[c]acridine, 7-methylbenz[c]acridine-5,6-oxide and phenols to be major products. Metabolite distributions obtained with lung microsomes were very similar although activities were much lower than those of liver microsomes prepared from the same animals.

Acridines↗
PubMedDate not supplied

Mutagenicity of selected functionalized benz(c)acridines and a benz(a)phenazine in the Salmonella typhimurium/microsome assay.

Five functionalized benz(c)acridines - 5,6-dimethylbenz(c)acridine; 5,6,7-trimethylbenz(c)acridine; 7-chloro-5,6-dimethylbenz(c)acridine; 7-amino-5,6-dimethylbenz(c)acridine; 7-oxo-5,6-dimethylbenz(c)-acridine and 5,6-dimethylbenz(a)phenazine - were tested for mutagenic activity in the Ames Salmonella typhimurium assay. Compounds were initially screened by spot tests with 5 tester strains and both plate incorporation and pre-incubation assays were performed when the results of the tests were positive or weakly positive. All assays were done with and without S9 activation. 7-Amino-5, 6-dimethylbenz(c)acridine and 7-chloro-5, 6-dimethylbenz(c)acridine were found to be moderately mutagenic with the 3 frameshift strains TA1537, TA98, and TA97.

Acridines↗
PubMed1995

DNA nick processing by exonuclease and polymerase activities of bacteriophage T4 DNA polymerase accounts for acridine-induced mutation specificities in T4.

Acridine-induced frameshift mutagenesis in bacteriophage T4 has been shown to be dependent on T4 topoisomerase. In the absence of a functional T4 topoisomerase, in vivo acridine-induced mutagenesis is reduced to background levels. Further, the in vivo sites of acridine-induced deletions and duplications correlate precisely with in vitro sites of acridine-induced T4 topoisomerase cleavage. These correlations suggest that acridine-induced discontinuities introduced by topoisomerase could be processed into frameshift mutations. The induced mutations at these sites have a specific arrangement about the cleavage site. Deletions occur adjacent to the 3' end and duplications occur adjacent to the 5' end of the cleaved bond. It was proposed that at the nick, deletions could be produced by the 3'-->5' removal of bases by DNA polymerase-associated exonuclease and duplications could be produced by the 5'-->3' templated addition of bases. We have tested in vivo for T4 DNA polymerase involvement in nick processing, using T4 phage having DNA polymerases with altered ratios of exonuclease to polymerase activities. We predicted that the ratios of the deletion to duplication mutations induced by acridines in these polymerase mutant strains would reflect the altered exonuclease/polymerase ratios of the mutant T4 DNA polymerases. The results support this prediction, confirming that the two activities of the T4 DNA polymerase contribute to mutagenesis. The experiments show that the influence of T4 DNA polymerase in acridine-induced mutation specificities is due to its processing of acridine-induced 3'-hydroxyl ends to generate deletions and duplications by a mechanism that does not involve DNA slippage.

Aminacrine↗
PubMed1991

The specificity of topoisomerase-mediated DNA cleavage defines acridine-induced frameshift specificity within a hotspot in bacteriophage T4.

Acridine-induced frameshift mutations in bacteriophage T4 occur at the precise location in the DNA at which acridines stimulate DNA cleavage by the T4-encoded type II topoisomerase in vitro. The mutations are duplications or deletions that begin precisely at the broken phosphodiester bond. In vivo, acridine-induced frameshift mutagenesis is reduced nearly to background levels when the topoisomerase is genetically inactivated. These observations are consistent with a model in which cleaved DNA, induced by the topoisomerase and acridine, serves as the substrate for the production of frameshift mutations at the same site. Our model predicts that the specificity and frequency of cleavage direct the specificity and frequency of mutagenesis. This prediction was tested by examining the influence of DNA sequence changes on topoisomerase-mediated cleavage and on mutagenesis in the T4 rIIB gene. The model successfully predicted the results. When DNA sequence changes altered the position of acridine-induced, topoisomerase-mediated DNA cleavage in vitro, frameshift mutations were found at the new positions. DNA sequence changes that strongly decreased in vitro cleavage also reduced mutagenesis at that site. These results demonstrate that acridine-induced frameshift mutation specificity is directed by the characteristics of the acridine-topoisomerase reaction and do not suggest that slipped pairing in repeated sequences plays a major role in acridine-induced frameshifts in bacteriophage T4.

Amsacrine↗
PubMed1981

The accumulation and disposition of benz(a)acridine in the fathead minnow, Pimephales promelas.

The bioconcentration and metabolism of benz(a)acridine in fathead minnows (Pimephales promelas) was investigated using 14C-labelled benz(a)acridine. The rates of uptake, elimination, and metabolic transformation of benz(a)acridine were estimated in the fish. The equilibrium concentration factor [ratio of benz(a)acridine concentration in fish (wet weight) to benz(a)acridine concentration in water] was estimated at 106 +/- 17. The observed bioconcentration factor was about one tenth of that predicted by octanol-water partitioning models. Metabolic alteration was estimated to reduce the degree of bioconcentration 50 to 90% from the hypothetical case in which metabolic transformation did not occur. Benz(a)acridine metabolites attained concentrations in the fish considerably in excess of benz(a)acridine itself.

Acridines↗
PubMed1994

Transport of acridine in saturated porous media.

The effects of the aqueous solution pH, temperature, initial solute concentration and non-equilibrium processes on the transport of acridine in saturated porous media (silica) were investigated in a series of continuous-flow column experiments. The enthalpy of the adsorption reaction was more exothermic when the solution pH was above acridine's pKa (5.6) than when it was below. The extent of adsorption was greater when the solution pH was below the pKa of acridine than when it was above. Non-equilibrium effects on the adsorption reaction were found to be unimportant at groundwater velocities. The results from this study suggest that the mobility of acridine in aquifers, in which adsorption to silica edge sites is significant, would increase as the temperature of the groundwater increased and the acridine mobility would be greatest when the pH of the groundwater is above the pKa of acridine. The transport of acridine in such aquifers can be effectively modeled using the local equilibrium assumption.

Acridines↗
PubMedDate not supplied

Recognition of hairpin-containing single-stranded DNA by oligonucleotides containing internal acridine derivatives.

Oligodeoxynucleotides with an internal intercalating agent have been targeted to single-stranded sequences containing hairpin structures. The oligonucleotide binds to nonadjacent single-stranded sequences on both sides of the hairpin structure in such a way as to form a three-way junction. The acridine derivative is inserted at a position that allows it to interact with the three-way junction. The melting temperature (Tm) of complexes formed between the hairpin-containing target and oligonucleotides containing one internal acridine derivative was higher than that obtained with the same target and an unmodified oligonucleotide (DeltaTm = +13 degrees C). The internal acridine provided the oligonucleotide with a higher affinity than covalent attachment to the 5' end. Oligonucleotides could also be designed to recognize a hairpin-containing single-stranded nucleic acid by formation of Watson-Crick hydrogen bonds with a single-stranded part and Hoogsteen hydrogen bonds with the stem of the hairpin. An internal acridine derivative was introduced at the junction between the two domains, the double helix domain with Watson-Crick base pairs and the triple helix domain involving Hoogsteen base triplets in the major groove of the hairpin stem. Oligonucleotides with an internal acridine or an acridine at their 5' end have similar binding affinities for the stem-loop-containing target. The bis-modified oligonucleotide containing two acridines, one at the 5' end and one at an internal site, did not exhibit a higher affinity than the oligonucleotides with only one intercalating agent. The design of oligonucleotides with an internal intercalating agent might be of interest to control gene expression through recognition of secondary structures in single-stranded targets.

Acridines↗
PubMed1986

Dibenz[a,j]acridine metabolism: identification of in vitro products formed by liver microsomes from 3-methylcholanthrene-pretreated rats.

The metabolism of the carcinogenic pentacyclic azaaromatic compound, dibenz[a,j]acridine, has been examined in liver microsomal incubations using preparations from 3-methylcholanthrene-pretreated Wistar rats. Using authentic synthetic standards, u.v. spectroscopy and mass spectrometry, the following were proved to be metabolites: trans-5,6-dihydro-5,6-dihydroxydibenz[a,j]acridine, trans-3,4-dihydro-3,4-dihydroxydibenz[a,j]acridine, dibenz[a,j]acridine-5,6-oxide, 3-hydroxydibenz[a,j]acridine and 4-hydroxydibenz[a,j]acridine. The 3,4-dihydrodiol appeared to be the major metabolite. The secondary metabolites were also examined and evidence is presented for the additional formation of dibenz[a,j]acridine-5,6,8,9-dioxide, tetrols, diol epoxides and phenolic dihydrodiols.

Acridines↗
PubMed2005

Acridine derivatives activate p53 and induce tumor cell death through Bax.

CP-31398 activates wild-type p53 by a novel mechanism that does not involve phosphorylation of the amino-terminus of p53 and disassociation of MDM2. To identify more potent CP-31398-like p53 activators, we synthesized 4 acridine derivatives with a similar structure to CP-31398. These four compounds induced strong p53 transcription in cells with wild-type p53. We also found that several randomly chosen acridine derivatives, including 9-aminoacridine, amsacrine, quinacrine and acridine orange, induced p53 transcriptional activity. All these acridine derivatives stabilized p53 protein by blocking its ubiquitination, without phosphorylation of ser15 or ser20 on p53. Furthermore, acridine derivatives induced p53-dependent cell death. Knockout of Bax, a p53 target and a key cell death inducer in both intrinsic and extrinsic apoptotic pathways, blocked acridine derivatives from inducing cell death. In addition, in vivo delivery of quinacrine and amsacrine induced p53 transcriptional activity in tumor xenografts. Our results reveal that DNA-intercalating acridine derivatives can induce p53 stabilization by a manner similar to CP-31398. These findings provide insights into p53 regulation in response to DNA intercalating drugs and may assist new anti-cancer drug design.

Acridines↗