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PubMed1996

Degradation of pyrene by Mycobacterium flavescens.

A strain of Mycobacterium flavescens was isolated from polluted sediments. It was capable of utilizing pyrene as a sole source of carbon and energy. When pyrene was supplied as a suspension at 50 micrograms/ml, the generation time was 9.6 h and the rate of pyrene utilization was 0.56 microgram ml-1 day-1. In addition to pyrene, the strain could mineralize phenanthrene (17.7%) and fluoranthene (17.9%), but failed to mineralize naphthalene, chrysene, anthracene, fluorene, acenaphthene and benzo[a]pyrene, as determined by recovery of radiolabeled CO2 in incubations conducted for 2 weeks under growth conditions. Metabolites produced during growth on pyrene were detected and characterized by HPLC and GC-MS. The product of initial ring oxidation, 4,5-dihydroxy-4,5-dihydropyrene was identified, as well as ring-fission products including 4-phenanthroic acid, phthalic acid, and 4,5-phenanthrenedioic acid.

Biodegradation, Environmental↗
PubMed1999

Degradation of phenanthrene by different bacteria: evidence for novel transformation sequences involving the formation of 1-naphthol.

Four polycyclic aromatic hydrocarbon (PAH)-degrading bacteria, namely Arthrobacter sulphureus RKJ4, Acidovorax delafieldii P4-1, Brevibacterium sp. HL4 and Pseudomonas sp. DLC-P11, capable of utilizing phenanthrene as the sole source of carbon and energy, were tested for its degradation using radiolabelled phenanthrene. [9-14C]Phenanthrene was incubated with microorganisms containing 100 mg/l unlabelled phenanthrene and the evolution of 14CO2 was monitored: within 18 h of incubation, 30.1, 35.6, 26.5 and 2.1% of the recovered radiolabelled carbon was degraded to 14CO2 by RKJ4, P4-1, HL4 and DLC-P11, respectively. When mixtures of other PAHs such as fluorene, fluoranthene and pyrene, in addition to phenanthrene, were added as additional carbon sources, there was a 36.1 and 20.6% increase in 14CO2 production from [9-14C]phenanthrene in the cases of RKJ4 and HL4, respectively, whereas P4-1 and DLC-P11 did not show any enhancement in 14CO2 production. Although, a combination of many bacteria enhances the degradation of organic compounds, no enhancement in the degradation of [9-14C]phenanthrene was observed in mixed culture involving all four microorganisms together. However, when different PAHs, as indicated above, were used in mixed culture, there was a 68.2% increase in 14CO2 production. In another experiment, the overall growth rate of P4-1 on phenanthrene could be enhanced by adding the non-ionic surfactant Triton X-100, whereas RKJ4, HL4 and DLC-P11 did not show any enhancement in growth. Pathways for phenanthrene degradation were also analysed by thin-layer chromatography, gas chromatography and gas chromatography-mass spectrometry. Common intermediates such as o-phthalic acid and protocatechuic acid were detected in the case of RKJ4 and o-phthalic acid was detected in the case of P4-1. A new intermediate, 1-naphthol, was detected in the cases of HL4 and DLC-P11. HL4 degrades phenanthrene via 1-hydroxy-2-naphthoic acid, 1-naphthol and salicylic acid, whereas DLC-P11 degrades phenanthrene via the formation of 1-hydroxy-2-naphthoic acid, 1-naphthol and o-phthalic acid. Both transformation sequences are novel and have not been previously reported in the literature. Mega plasmids were found to be present in RKJ4, HL4 and DLC-P11, but their involvement in phenanthrene degradation could not be established.

Bacteria↗
PubMed1999

Dermal exposure assessment of polycyclic aromatic hydrocarbons: in vitro percutaneous penetration from lubricating oil.

OBJECTIVES: Percutaneous penetration of polycyclic aromatic hydrocarbons (PAHs) is affected by various factors connected to exposure conditions. The nature of the matrix, such as that of oil, can strongly affect their percutaneous penetration. Risk assessment should consider these effects. We examined the effect of matrix on percutaneous penetration of PAHs, particularly that of lubricating oil. METHODS: The test apparatus consisted of an in vitro static diffusion cell system using full-thickness monkey (Cercopithecus aetiops) skin as the membrane and saline solution with gentamycin sulfate and 4% bovine serum albumin as receptor fluid. Chemical analysis of PAHs in the samples obtained from cells was carried out by inverse-phase HPCL, and the results were read by spectrofluorimetry. RESULTS: Comparing the penetration of 13 PAHs from a lubricating oil and from acetone solution with artificial sweat resulted in a significantly slower passage from the oil matrix for acenaphthene, anthracene, phenanthrene, fluoranthene, naphthalene, pyrene, fluorene (Mann-Whitney U test, P < 0.05). No significant differences in the passage were found for chrysene because, in the test with oil, its concentration was very often below the detection limit. For benzo[a]anthracene, benzo[b]fluoranthene, benzo[k]fluoranthene, and benzo[a]pyrene it was possible to demonstrate a passage through the skin only when compounds were applied in acetone solution with artificial sweat. CONCLUSIONS: The results of the study suggest the necessity of dermal penetration data relevant for risk assessment, obtained under experimental conditions similar to the real exposure conditions.

Acetone↗
PubMed2000

Indoor exposure to polycyclic aromatic hydrocarbons and carbon monoxide in traditional houses in Burundi.

OBJECTIVES: Wood combustion is used as a major energy source in African countries and could result in indoor, pollution-related health problems. This exploratory study was undertaken to estimate polycyclic aromatic hydrocarbon (PAH) and carbon monoxide exposure in individuals living in traditional rural houses in Burundi. METHODS: Standard methods were used to determine indoor air concentrations of 12 PAHs, and carbon monoxide. The urinary excretion of 1-hydroxypyrene (1-OHP) was measured in occupants of traditional houses, and compared with that of individuals living in the town of Bujumbura, the capital of Burundi. RESULTS: Mean airborne concentration of four volatile PAHs, naphthalene, fluorene, phenanthrene and acenaphthene, exceeded 1 microg/m3, and that of benzo(a)pyrene was 0.07 microg/m3. Naphthalene was by far the main PAH contaminant, with a mean concentration (+/- standard deviation) of 28.7+/-23.4 microg/m3, representing on average 60-70% of total PAH concentration. Carbon monoxide mean concentration (+/- standard deviation) was 42+/-31 mg/m3, and correlated with total PAH concentration. Geometric mean urinary 1-OHP excretion (range) in people living in traditional houses was 1.50 (0.26-15.62) micromol/mol creatinine, a value which is on average 30 times higher than that of people living in the capital (0.05 (0.009-0.17) micromol/mol creatinine). CONCLUSIONS: It appears that the substantially high concentrations of the studied contaminants constitute a potential health hazard to the rural population of Burundi.

Adolescent↗
PubMed2003

Microbial characterization and hydrocarbon biodegradation potential of natural bilge waste microflora.

Shipping operations produce oily wastes that must be managed properly to avoid environmental pollution. The aim of this study was to characterize microorganisms occurring in ship bilge wastes placed in open lagoons and, particularly, to assess their potential to degrade polycyclic aromatic hydrocarbons (PAHs). A first-order kinetic was suitable for describing hydrocarbon biodegradation after 17 days of treatment. The calculated rate constants were 0.0668 and 0.0513 day(-1) with a corresponding half-life of 10.3 and 13.5 days for the aliphatic and aromatic hydrocarbon fractions, respectively. At day 17, PAH removal percentages were: acenaphtylene 100, fluorene 95.2, phenanthrene 93.6, anthracene 70.3, and pyrene 71.5. Methyl phenanthrene removals were lower than that of their parent compound (3-methyl phenanthrene 83.6, 2-methyl phenanthrene 80.8, 1-methyl phenanthrene 77.3, 9-methyl phenanthrene 75.1, and 2,7-dimethyl phenanthrene 76.6). Neither pure cultures nor the microbial community from these wastes showed extracellular biosurfactant production suggesting that the addition of an exogenously produced biosurfactant may be important in enhancing hydrocarbon bioavailability and biodegradation. DNA analysis of bilge waste samples revealed a ubiquitous distribution of the nahAc genotype in the dump pools. Although almost all of the isolates grew on naphthalene as sole carbon source, only some of them yielded nahAc amplification under the experimental conditions used. The variety of PAHs in bilge wastes could support bacteria with multiple degradation pathways and a diversity of catabolic genes divergent from the classical nah-like type.

Biotechnology↗
PubMed2005

Isolation and characterization of phenanthrene-degrading Sphingomonas paucimobilis strain ZX4.

Phenanthrene-degrading bacterium strain ZX4 was isolated from an oil-contaminated soil, and identified as Sphingomonas paucimobilis based on 16S rDNA sequence, cellular fatty acid composition, mol% G + C and Biolog-GN tests. Besides phenanthrene, strain ZX4 could also utilize naphthalene, fluorene and other aromatic compounds. The growth on salicylic acid and catechol showed that the strain degraded phenanthrene via salicylate pathway, while the assay of catechol 2,3-dioxygenase revealed catechol could be metabolized through meta-cleavage pathway. Three genes, including two of meta-cleavage operon genes and one of GST encoding gene were obtained. The order of genes arrangement was similar to S-type metapathway operons. The phylogenetic trees based on 16S rDNA sequence and meta-pathway gene both revealed that strain ZX4 is clustered with strains from genus Sphingomonas.

Amino Acid Sequence↗
PubMed2006

Toxicological characterisation of the aqueous soluble phase of the Prestige fuel-oil using the sea-urchin embryo bioassay.

The soluble components of fuel oil are generally assumed to be the fraction that is toxic for organisms living in the water column. We have used a liquid phase bioassay with embryos of sea urchin to assess the toxicity of the water-soluble fraction (elutriate) of the fuel oil spilled when the tanker Prestige sank on 13 November 2002. Two methodologies to obtain elutriates were carried out in order to compare the effect of the extraction method on the measured toxicity. Analyses of Sigma16PAHs (naphthalene, acenaphtylene, acenaphthene, fluorene, phenanthrene, anthracene, fluoranthene, pyrene, benz(a)anthracene, chrysene, benzo(b)fluoranthene, benzo(k)fluoranthene, Indeno(1,2,3-c-d)pyrene, benzo(a)pyrene, dibenz(a,h)anthracene and benzo(ghi)perylene) and four metals (copper, cadmium, lead and zinc) were conducted and linked to the biological response. The effective concentration that provoked a delay in the successful embryogenesis of 50% of population (EC50) was 2.3% of fuel oil. No differences in final toxicity between the two elutriation treatments were found, although the rotated extraction seemed to be more effective than magnetic stirring in transferring contaminants from the fuel oil to the water. Toxicity was mainly associated with the low-weight PAHs (2-4 benzene rings).

Animals↗
PubMedDate not supplied

Spatial distribution of PAHs in a contaminated valley in Southeast China.

A survey was conducted on the accumulation and spatial distribution of PAHs in surface soils under different land use patterns in a valley in the Yangtze Delta region with an area of 10 km(2) containing 15 small copper- and zinc-smelting furnaces. Sixty-five topsoil (0-20 cm) samples were collected and 16 PAHs were determined. The average amount of all the 16 PAHs ranged from 0 to 530 microg kg(-1) (oven dry basis), with a mean concentration of 33.2 microg kg(-1). Benzo[a]pyrene and indeno[1, 2, 3, -cd]pyrene were the two main PAHs present at high concentrations, while pyrene and fluorene had very low concentrations. PAH concentrations were higher in uncultivated than in cultivated soils, and areas of woods and shrubbery had the lowest soil PAH contents. The average PAH-homologue concentrations ranked as follows: 5-rings >> 3-rings, 4-rings > 6-rings >2-rings. Much higher concentrations of PAHs were found in the southern part of the sampling area, perhaps due to deposition of airborne particles by the southeasterly winds in winter and spring. We conclude that the small smelting furnaces were the dominant source of PAHs that accumulated in the soils and the southeasterly winds led to the spatial distribution of PAHs in the topsoils. Land vegetation cover and soil utilization patterns also affected the accumulation and distribution of soil PAHs.

China↗
PubMed2006

Analysis of polycyclic aromatic hydrocarbons in street soil dust in Kumasi Metropolis of Ghana.

Concentrations of polycyclic aromatic hydrocarbons (PAHs) in street soil dust from streets in Kumasi Metropolis in the Ashanti Region of the Republic of Ghana have been measured in this study. The concentrations of the various types of PAHs identified in this study are as follows: Naphthalene (m/e 128) - 41,700 microg/kg, Acenaphthylene (m/e 152) - 99,300 microg/kg, Acenaphthene (m/e 154) - 111,200 microg/kg, Fluorene (m/e 166) - 8,900 microg/kg, Carbazole (m/e 167) - 3,500 microg/kg, phenathrene (m/e 178) - 12,900 microg/kg, Anthracene (m/e 178) - 5,400 microg/kg, Fluoranthene (m/e 202) - 16,200 microg/kg, Pyrene (m/e 202) - 15,000 microg/kg, Benzo[a]anthracene (m/e 228) - 13,800 microg/kg, Chrysene (m/e 228) - 33,600 microg/kg, Benzo[k]fluoranthene (m/e 252) - 45,700 microg/kg, Benzo[a]pyrene (m/e 252) - 27,900 microg/kg, Perylene (m/e 252) - 57,200 microg/kg and Benzo[g, h, i]perylene (m/e 276) - 47,000 microg/kg. The results of the study shows that road users, like resident living in buildings within these areas, those engaged in commercial activities like hawking, and the general public are at risk of exposure to the toxic effects of the various types of PAHs from the exhaust of vehicles into the environment. According to these results, there is the potential for exposure to high levels of PAHs for road users and those living in urban environments or along highways.

Air Pollutants↗
PubMed2007

Identification and biochemical studies on novel non-nucleoside inhibitors of the enzyme adenosine kinase.

The enzyme adenosine kinase (AK) plays a key role in the regulation of intracellular and extracellular concentration of adenosine (Ado), which exhibits potent hormonal activity in cardiovascular, nervous and immune systems. In view of the pharmacological effects of Ado, there is much interest in identifying inhibitors of AK, which can augment its tissue-protective effects. In this study, we have screened 1040 compounds from a chemical library of putative kinase inhibitors for their effect on purified human recombinant AK. These studies have identified 8 novel, non-nucleoside AK inhibitors. Four of these compounds (viz. 2-tert-butyl-4H-benzo[1,2,4]thiadiazine-3-thione (2759-0749); N-(5,6-diphenyl-furo[2,3-d]pyrimidin-4-yl)-propionamide (3998-0118); 3-[5,6-Bis-(4-methoxy-phenyl)-furo[2,3-d]pyrimidin-4-ylamino]-propan-1-ol (4072-2732); and 2-[2-(3,4-dihydroxy-phenyl)-5-phenyl-1H-imidazol-4-yl]-fluoren-9-one (8008-6198)), which inhibited human AK in a concentration-dependent manner in a low micromolar range (IC(50) = 0.38 approximately 1.98 microM) were further studied. Kinetic and structural studies on these compounds provide evidence that inhibition of AK by these compounds was competitive with respect to Ado and non-competitive for ATP. All of these compounds also inhibited uptake of Ado and its metabolism in cultured mammalian cells at comparable concentrations indicating their efficient cellular penetrability. These AK inhibitors, whose chemical structures differ significantly from all previously known inhibitors, provide useful lead compounds for identification of more potent but less toxic AK inhibitors that may prove useful for therapeutic purposes.

Adenosine↗
PubMed1983

Sensitive fluorographic detection of 3H and 14C on chromatograms using methyl anthranilate as a scintillant.

Methyl anthranilate is a simple, sensitive, and inexpensive liquid scintillant for fluorographic detection of weak beta-emitting isotopes on chromatograms. Detection of tritium is enhanced 1000-fold compared to autoradiography in a 24-h exposure. Since methyl anthranilate is a viscous liquid, it is easily applied as an even coating which subsequently solidifies at the low temperature (-80 degrees C) used for fluorography. Of several liquid scintillants tested, methyl anthranilate was most effective, followed by 9-ethyl fluorene, methyl salicylate, and 1-methyl naphthalene. The efficiency of 1-methyl naphthalene could be raised to the level of methyl anthranilate by the addition of a small amount (0.5%) of 2,5-diphenyloxazole (PPO).

Autoradiography↗
PubMed1990

Large-scale purification of synthetic oligonucleotides and carcinogen-modified oligodeoxynucleotides on a reverse-phase polystyrene (PRP-1) column.

A procedure is described for the large-scale purification of synthetic oligonucleotides using a polystyrene (PRP-1, Hamilton Co.) high-performance liquid chromatography (HPLC) column with a phosphate/methanol/acetonitrile solvent system. Pure oligonucleotides are obtained with a three-step procedure that involves only one column purification step. The dimethoxytrityl group is left on the oligomer for the HPLC purification. The use of the PRP-1 polystyrene column with a phosphate/methanol/acetonitrile solvent system provides excellent separation of the desired dimethoxytrityl-bearing oligonucleotide from failure sequences. The dimethoxytrityl group is removed by treatment with acetic acid and the oligonucleotide is desalted on a C-18 Sep-Pak cartridge. The oligodeoxynucleotides obtained are shown to be essentially pure by HPLC, polyacrylamide gel electrophoresis, and 500-MHzNMR spectroscopy. This procedure is especially useful for the large-scale purification of oligonucleotides required for NMR studies. The PRP-1 column and the phosphate/methanol/acetonitrile solvent system is useful for purifying modified oligonucleotides containing lipophilic groups such as the carcinogen 2-(acetylamino)fluorene.

Base Sequence↗
PubMed1991

Nuclease P1-mediated fluorescence postlabeling assay of AAF modified DNA model d(TACGTA) and calf-thymus DNA.

Fluorescence postlabeling assay for DNA damage combines enzymatic digestion of modified DNA to nucleoside monophosphates and fluorescence postlabeling. However, to facilitate the quantitative release of bulky adducts that are not readily obtained as mononucleotides, a different mechanism is essential. In order to test the application potential of nuclease P1-mediated fluorescence postlabeling to assay bulky adduct, d(TACGTA) was reacted with N-acetoxy-2-acetylamino-fluorene. The major product, characterized by nmr as AAF adduct of the guanine moiety at the C-8 position, was used as a DNA model. Nuclease P1 digestion of the modified oligomer excised the adduct in two forms (3:1) which were identified as AAF modified d(pGpT) and dpG respectively by cochromotography with authentic markers. Fluorescence postlabeling assay of AAF modified d(TACGTA) detected both forms of the excised adduct. The application of the overall procedure to assay AAF modified calf-thymus DNA demonstrated that the extension of fluorescence postlabeling technique from the mononucleotide to the dinucleotide version expands the scope of the assay.

Acetoxyacetylaminofluorene↗
PubMed1985

Assessment of rat liver microsomal epoxide hydrolase as a marker of hepatocarcinogenesis.

The influence of eleven xenobiotics on the activity and amount of hepatic microsomal epoxide hydrolase was determined. Activity was assayed using three different substrates after rats were fed, throughout 3 weeks, diets containing one of six hepatocarcinogens, viz. 2-acetylaminofluorene, 3'-methyl-4-dimethylaminoazobenzene, 4'-fluoro-4-dimethylaminoazobenzene, thioacetamide, aflatoxin B1 and ethionine. Five hepatocarcinogens induced activity 4- to 10-fold; ethionine was relatively ineffective as an inducer. Two non-carcinogenic analogues of hepatocarcinogens, viz. fluorene and p-aminoazobenzene, caused no appreciable increase in enzyme activity, but phenobarbital, barbital and 1-naphthylisothiocyanate induced activity 2- to 3-fold. All eleven xenobiotics increased the amount of microsomal epoxide hydrolase 2- to 9-fold when examined immunochemically using either a radial diffusion assay or an enzyme-linked immunosorbent assay (ELISA). Serum glutamic oxaloacetic acid transaminase activity was not appreciably elevated by feeding ten of the xenobiotics, suggesting that inductions were not owing to toxicity. Using ELISA, microsomal epoxide hydrolase was detected in post-microsomal (PM) supernatant fractions from control rat liver, thus confirming an earlier report by Gill et al. [Carcinogenesis 3, 1307 (1982)]. The eleven xenobiotics induced the amount of ELISA-detectable antigen in PM supernatant fractions by 3- to 34-fold. Longer centrifugation of PM supernatant fractions yielded a pellet fraction that contained 92 +/- 1.2% of the ELISA-detectable antigen irrespective of the xenobiotic regimen. Relationships between xenobiotic induction of microsomal epoxide hydrolase activity and amount and hepatocarcinogenesis are discussed.

Animals↗
PubMed1989

Immunodetection, immunoinhibition, immunoquantitation and biochemical analyses of cytochrome P-450IA1 in tissues of the ratoffceptus during the progression of organogenesis.

Polyclonal antibodies raised against the adult form of rat hepatic cytochrome P-450IA1 were used to immunologically detect, inhibit and quantitate an analogous isozymic form(s) in various tissues of the rat conceptus during the progression of organogenesis. Tissues investigated were the embryo proper, the visceral yolk sac and the ectoplacental cone/chorioallantoic placenta. Studies were performed on conceptuses from day 10 (day of conception = day 0) to day 14 of gestation. Ethoxyphenoxazone deethylation, benzo[a]pyrene (BaP) hydroxylation, and ring- and N-hydroxylation of 2-acetylamino-fluorene (AAF) were utilized in assessments of cytochrome P-450IA1-dependent monooxygenase activities during the same gestational period. In untreated conceptuses, cytochrome P-450IA1 could not be detected immunologically in any of the three tissues at any stage of gestation investigated. The deethylation reaction was quantifiable in embryos and yolk sacs of untreated conceptuses, but was not inhibited by cytochrome anti-P-450IA1 antibodies, alpha-naphthoflavone or metyrapone. Treatment of pregnant rats with 40 mg/kg of 3-methylcholanthrene 48 hr prior to removal of the conceptuses resulted in marked increases in measured enzymatic activities as well as in readily immunodetectable cytochrome P-450IA1. Inducibility for the deethylase was greatest in the visceral yolk sac (3-8x), was evident in the embryo proper (2-3x) but was minimal in the ectoplacental cone (1.5-2x). Much greater induction (up to 70x) was observed with BaP and AAF as substrates. Induced activities were inhibited effectively (70-100% inhibition) by cytochrome anti-P-450IA1 antibodies and by alpha-naphthoflavone but not by metyrapone. Inducibility increased as a function of gestational age in the ectoplacental cone/chorioallantoic placenta but reached maxima on day 12 in the embryo and visceral yolk sac. A good correlation between antibody/alpha-naphthoflavone-inhibited enzymatic activities and quantities of immuno-detectable cytochrome P-450IA1 was also apparent. The results indicate that cytochrome P-450IA1, or a very closely related isoform(s), is both inducible and enzymatically functional in tissues of the conceptus throughout organogenesis and have important implications for the potential effects of bioactivatable proteratogens.

2-Acetylaminofluorene↗
PubMed1992

Chronic physical activity: hepatic hypertrophy and increased total biotransformation enzyme activity.

Does chronic voluntary physical activity alter hepatic or intestinal capacities for xenobiotic biotransformation? This question was investigated by comparing biotransformation enzyme activities in liver and small intestine of active and sedentary rats. Male rats allowed unlimited access to a running wheel and fed ad lib. for 6 weeks were weight-matched to sedentary controls; the active rats ate 22% more food than the sedentary rats (P less than 0.05). Active rats ran 2.8 +/- 0.6 miles/day. Liver weights were higher in the active rats (11.2 +/- 0.2 vs 9.8 +/- 0.2 g; P less than 0.05), as were total liver protein, and liver microsomal and cytosolic protein (P less than 0.05). As a result of liver hypertrophy, the active rats showed higher total liver activity of several biotransformation enzymes, including 2-naphthol sulfotransferase, styrene oxide hydrolase, benzphetamine N-demethylase, ethacrynic acid glutathione S-transferase and morphine UDP-glucuronosyltransferase (P less than 0.05). In contrast, there was no detectable difference in total liver N-acetyltransferase activity toward p-aminobenzoic acid, 2-naphthylamine, and 2-amino-fluorene as well as, relative hepatic enzyme activity (expressed per g liver or per mg protein) and total and relative intestinal enzyme activity. We conclude that chronic voluntary physical activity, accompanied by an increased food intake, results in liver hypertrophy and potentially increases total hepatic capacity to biotransform certain xenobiotic chemicals.

Animals↗
PubMed1993

Effect of NPC 15669, an inhibitor of neutrophil recruitment and neutrophil-mediated inflammation, on neutrophil function in vitro.

The new anti-inflammatory agent N-[9H-(2,7-dimethylfluorenyl-9-methoxy)carbonyl]-L-leucine (NPC 15669) inhibits inflammation in several animal models dependent upon neutrophil activation and recruitment into the inflammatory lesion. NPC 15669 appears to elicit its pharmacological action by inhibiting the cell surface expression of CD11b/CD18 (Mac-1) on the neutrophil and subsequent adhesion of the neutrophil to the vascular endothelium. The current study sought to further characterize the action of NPC 15669 on neutrophil function. In the range of 1-100 microM, this fluorene enhanced superoxide production in a concentration-dependent fashion. Using spin trapping/ESR spectroscopy, NPC 15669 was found to inhibit myeloperoxidase (MPO)-dependent hydroxyl radical primarily by scavenging hypochlorous acid, and secondarily by inhibiting agonist-stimulated degranulation as assessed by MPO and elastase release. These studies demonstrated that NPC 15669, in addition to inhibiting adhesion, alters other neutrophil functions. Whether the pharmacological activities described for NPC 15669 resulted directly from changes in Mac-1 expression or through some other mechanism is currently under investigation.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1995

Tilorone-induced lysosomal storage of sulphated glycosaminoglycans can be separated from tilorone-induced enhancement of lysosomal enzyme secretion.

This investigation deals with a drug side-effect. The immunomodulatory drug tilorone (2,7-bis[2-(diethylamino)ethoxy]fluoren-9-one) and congeners induce lysosomal storage of sulphated glycosaminoglycans (GAGs) in animals and in cultured cells. At high tilorone concentrations, GAG storage in cultured fibroblasts was previously reported to be accompanied, and presumably caused by, disturbance of intracellular targeting of lysosomal enzyme precursors, which leads to enhanced secretion and thus loss of lysosomal enzymes. The purpose of the present study was to examine whether the GAG storage induced in cultured bovine fibroblasts by low tilorone concentrations is also accompanied by enhanced lysosomal enzyme release. Enhanced secretion of beta-hexosaminidase (EC 3.2.1.52) was taken as indicating the intracellular mistargeting of lysosomal enzyme precursors. Dose-response curves were established for (a) the intracellular accumulation of 35S-GAGs and (b) the release of beta-hexosaminidase after exposure (72 hr) to tilorone (1-35 microM). For positive controls, the classical lysosomotropic agents NH4Cl (1-30 mM) and chloroquine (1-60 microM) were used. With NH4Cl, 35S-GAG storage was accompanied by enhanced enzyme release throughout the concentration range (EC50 at 3.3 mM for either effect). With chloroquine, low concentrations (< or = 5 microM) caused a small increase in 35S-GAG accumulation without abnormal enzyme secretion; at higher concentrations both drug effects were produced (EC50 around 15 microM for either effect). With tilorone, low concentrations (< or = 5 microM) caused marked 35S-GAG accumulation without enhancement of enzyme release. The EC50 for tilorone-induced 35S-GAG storage was 3 microM, as opposed to 15 microM for enzyme release. The results indicate that GAG storage induced by low concentrations of tilorone is due to mechanisms other than mistargeting and loss of lysosomal enzymes. On the basis of previous results it may be hypothesized that tilorone and other symmetrically substituted dicationic compounds form complexes with the polyanionic GAG chains and thereby impair their enzymic degradation.

Ammonium Chloride↗