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PubMed2006

Differential role of 5-HT1A and 5-HT1B receptors on the antinociceptive and antidepressant effect of tramadol in mice.

RATIONALE: Tramadol, (1RS,2RS)-2-[(dimethylamine)-methyl]-1-(3-methoxyphenyl)-cyclohexanol hydrochloride, is an atypical analgesic which binds weakly to ì-opioid receptors and enhances the extra-neuronal concentration of noradrenaline and serotonin by interference with both the uptake and release mechanisms. OBJECTIVES: The present study was undertaken to evaluate the potential role of 5-HT1A and 5-HT1B receptors on the analgesic and antidepressant-like effect of tramadol. METHODS: The effect of either a selective 5-HT1A receptor antagonist (WAY 100635; N-2-[4-(2-methoxyphenyl-1-piperazinyl]ethyl]-N-2-pyridinylcyclohexane carboxamide; 0.2-0.8, 8 mg/kg) or a selective 5-HT1B receptor antagonist (SB 216641; N-[3-(3-dimethylamino) ethoxy-4-methoxyphenyl]-2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)-(1,1'-biphenyl)-4-carboxamide; 0.2-0.8, 8 mg/kg) was investigated in mice in combination with tramadol by means of the hot-plate test, a phasic nociceptive model, and the forced swimming test, a paradigm aimed at screening potential antidepressants. RESULTS: The results showed that WAY 100635 enhanced the antinociceptive effect and produced a large decrease in the antidepressant-like effect of tramadol. In contrast, SB 216641 did not significantly modify either the analgesic or the antidepressant-like effects of tramadol. CONCLUSIONS: These findings suggest that 5-HT1A receptors modulate the analgesic and the antidepressant-like effects of tramadol in differing ways. The results suggest the involvement of the 5-HT1A autoreceptors from the raphe nuclei and spinal 5-HT1A receptors in the antinociceptive effect. In contrast, the 5-HT1A receptors located in the forebrain may be responsible for the blockade of the antidepressant-like effect of tramadol. 5-HT1B receptors seem not to modify these effects in the models investigated.

Analgesics↗
PubMed2002

Modulation of cytosolic calcium levels in osteoblast-like osteosarcoma cells by olpadronate and its amino-derivative IG-9402.

The molecular mechanisms as well as the structure/activity relationships involved in the antiresorptive actions of bisphosphonates on bone cells are still not clear. Replacement of the R1-hydroxyl by an NH2 group in olpadronate (OPD) abolishes its antiresorptive activity. We show here that in the rat osteosarcoma-derived osteoblast-like ROS 17/2.8 cell line, OPD and IG-9402 (NH2-OPD; [3-(N,N-dimethylamine)-1-aminopropylidene bisphosphonate]), similar to 1,25(OH)2-vitamin D3, rapidly modulate cytosolic calcium levels ([Ca2+]i). As for the steroid hormone, the osteosarcoma cell Ca2+i response to OPD was rapid (30 sec) and sustained (>5 min), exhibiting a biphasic profile. The response to IG-9402 was also fast but smaller than that of OPD and 1,25(OH)2D3, and rapidly declined to levels near basal. The effect of these bisphosphonates on [Ca2+]i was dose-dependent, being maximal at 10(-8) M and was not observed in non-bone cellular systems, e.g., skeletal muscle and breast cells. Pretreatment of the ROS 17/2.8 cells with the Ca2+ channel blockers nifedipine and verapamil markedly reduced (>70%) the influx phase of the response to OPD and almost completely inhibited that of IG-9402, indicating the participation of voltage-dependent Ca2+ channels in the action of both compounds. Moreover, preincubation with the phospholipase C inhibitors U73122 and neomycin or depletion of inner stores with thapsigargin completely blocked the response to either olpadronate or its amino-derivative. Both OPD and IG-9402 significantly increased osteocalcin release into the culture medium of osteosarcoma cells. The results support the involvement of the Ca2+ signaling pathway as part of the mechanism by which bisphosphonates induce bone cellular responses.

Animals↗
PubMed1997

Phylogenetic and narG analysis of a Hyphomicrobium isolate.

An obligately methylotrophic organism was isolated from a water well that manifested symptoms of biofouling. The isolate was appendaged and utilized methylamine, dimethylamine, trimethylamine, or methanol as the sole carbon and energy source. The isolate exhibited hydroxypyruvate reductase activity, suggesting C1-assimilation via the serine pathway. Fatty acid profiling indicated the predominance of 18:1 cis-fatty acids. The isolate did not grow anaerobically with nitrate as the final electron acceptor. Genomic DNA from the isolate did not hybridize against the narG gene, which encodes the alpha subunit of dissimilatory nitrate reductase in Escherichia coli. The phenotypic data suggested the assignment of the isolate to the genus Hyphomicrobium. The identification was supported by phylogenetic characterization based on 16S rRNA sequence comparisons of the isolate.

Bacteria↗
PubMed2006

From chemosensory thresholds to whole body exposures-experimental approaches evaluating chemosensory effects of chemicals.

OBJECTIVES: To ensure safety and health the avoidance of adverse chemosensory effects is essential at workplaces where volatile chemicals are used. The present study describes psychophysical approaches that provide information for the evaluation of such effects. METHODS: By means of a modified staircase procedure the odor (OT) and irritation thresholds (IT) of 15 irritants were determined. These basic chemosensory properties, confining the chemosensory effect range, were investigated in a random sample of 144 persons stratified for gender and age. Those irritants exhibiting high chemosensory potency were selected for the second psychophysical part of the study. Forty-eight persons, again stratified for gender and age, rated the intensity of 13 trigeminal and olfactory perceptions elicited by nine ascending concentrations of the irritants, ranging from the odor to the irritation threshold of the respective substances. RESULTS: Across the investigated chemicals the transition from concentrations eliciting pure olfactory stimulation (OT) to trigeminal stimulation (IT) differed markedly. The carboxylic acids yielded narrow ranges from odor to irritation thresholds, while for the amines (cyclohexylamine, dimethylamine, and trimethylamine) and the esters (ethyl formate and ethyl acetate) these ranges were somewhat wider. The two chemosensory thresholds of ethyl acrylate and ammonia were farthest from each other. Gender and age had only weak impact on the chemosensory thresholds. At present, the results of the intensity ratings could be given for six substances. Among them, the rated pungency for cyclohexylamine, formic acid, and ethyl acetate increased strongest across the nine applied concentrations. CONCLUSIONS: By means of these psychophysical approaches a diverse class of chemicals can be described and compared with respect to their chemosensory potency. This information can be used twofold (a) for the evaluation of existing studies reporting sensory irritations and (b) for the design of experimental exposure studies.

Adolescent↗
PubMed2005

The energy metabolism of Methanomicrococcus blatticola: physiological and biochemical aspects.

Methanomicrococcus blatticola, a methanogenic archaeon isolated from the cockroach Periplaneta americana, is specialised in methane formation by the hydrogen-dependent reduction of methanol, monomethyl-, dimethyl- or trimethylamine. Experiments with resting cells demonstrated that the capability to utilise the methylated one-carbon compounds was growth substrate dependent. Methanol-grown cells were incapable of methylamine conversion, while cells cultured on one of the methylated amines did not metabolise methanol. Unlike trimethylamine, monomethyl- and dimethylamine metabolism appeared to be co-regulated. The central reaction in the energy metabolism of all methanogens studied so far, the reduction of CoM-S-S-CoB, was catalysed with high specific activity by a cell-free system. Activity was associated with the membrane fraction. Phenazine was an efficient artificial substrate in partial reactions, suggesting that the recently discovered methanophenazine might act in the organism as the physiological intermediary electron carrier. Our experiments also showed that M. blatticola apparently lacks the pathway for methyl-coenzyme oxidation to CO2, explaining the strict requirement for hydrogen in methanogenesis and the obligately heterotrophic character of the organism.

Animals↗
PubMed2005

Tamoxifen-induced cell death and expression of neurotrophic factors in cultured C6 glioma cells.

The effects of ( Z)-2[ p -(1,2-diphenyl-1-butenyl)phenoxy]-N ,N -dimethylamine citrate (tamoxifen) on cell survival and the expression of neurotrophic factors (NTF) were investigated in rat C6 glioma cells (C6). C6 cells do not express the estrogen receptor. Cytotoxic effect was detected from 24 h after the treatment with 10 microM tamoxifen and increased with time in a dose-dependent manner. C6 cells treated with tamoxifen also displayed various morphological types such as elliptical, round and aggregated form. As the treatment time increased, the proliferation of C6 cells was reduced remarkably and most of them became the round or aggregated form. To examine the relationship of the expression of NTF and the cytotoxicity of tamoxifen, the mRNA level of brain-derived neurotrophic factor (BDNF), glial-derived neurotrophic factor (GDNF), and basic fibroblast growth factor (bFGF) was measured after 24 h treatment with tamoxifen by RT-PCR. The expression of mRNA of BDNF or GDNF in C6 cells treated with various concentrations of tamoxifen was comparable to controls. The expression of bFGF mRNA was significantly reduced in C6 cells treated with 10 or 15 microM tamoxifen. The results suggest that tamoxifen exerts cytotoxic effect on estrogen receptor-negative C6 cells through the inhibition of the transcription of bFGF.

Animals↗
PubMed1985

Quantitative determination of methylamines using microelectrodes.

A new method for measuring methylamino compounds such as choline, trimethylamine, trimethylamine-N-oxide, betaine, L-carnitine, and dimethylamine is described. A glass microelectrode is used to quantify methylamines in concentrations ranging from 0.1 to 10.0 mM. Rapid time response and a good sensitivity are maintained by the microelectrode even when measurements are performed in solutions having high ionic strength and low pH. These characteristics make this assay suitable for use with conventional column chromatographic techniques of separation for these methylamines.

Calibration↗
PubMed1986

Optimization of erythrocyte membrane glycoprotein fluorescent labeling with dansylhydrazine after polyacrylamide gel electrophoresis.

An improved procedure for the labeling of glycoproteins with dansylhydrazine subsequent to electrophoresis in polyacrylamide gels is reported. This procedure is derived from the work of Eckhardt et al. (1976, Anal. Biochem. 73, 192-197) and Weber and Hof (1975, Biochem. Biophys. Res. Commun. 65, 1298-1302) who showed that dansylhydrazine may be condensed with the aldehyde groups of oxidized glycoprotein carbohydrates and the resulting hydrazones reduced with dimethylamine borane and/or sodium borohydride. Using the known distribution of erythrocyte membrane glycoproteins as a benchmark the effect of variation of a number of process parameters was investigated and an optimal procedure identified. The procedure is shown to be relatively insensitive to moderate variations in reagent composition, pH, and time of incubation with dansylhydrazine solution or reducing agents. It is also shown that labeling patterns may be preserved in dried gels if dimethylsulfoxide is replaced or omitted from all of the process solutions and destaining is effected with 1 M sodium acetate, pH 5.6. While specifically developed for the labeling of erythrocyte membrane proteins, the procedure is demonstrated to be applicable to other glycoprotein containing preparations.

Dansyl Compounds↗
PubMed1985

Reactions of nitrogen dioxide in aqueous model systems: oxidation of tyrosine units in peptides and proteins.

By application of pulse radiolysis it was demonstrated that nitrogen dioxide (NO2.) oxidizes Gly-Tyr in aqueous solution with a strongly pH-dependent rate constant (k6 = 3.2 X 10(5) M-1 S-1 at pH 7.5 and k6 = 2.0 X 10(7) M-1 S-1 at pH 11.3), primarily generating phenoxyl radicals. The phenoxyl can react further with NO2. (k7 approximately 3 X 10(9) M-1 S-1) to form nitrotyrosine, which is the predominant final product in neutral solution and at low tyrosyl concentrations under gamma-radiolysis conditions. Tyrosine nitration is less efficient in acidic solution, due to the natural disproportionation of NO2., and in alkaline solutions and at high tyrosyl concentrations due to enhanced tyrosyl dimerization. Selective tyrosine nitration by interaction of NO2. with proteins (at pH 7 to 9) was demonstrated in the case of histone, lysozyme, ribonuclease A, and subtilisin Carlsberg. Nitrotyrosine developed slowly also under incubation of Gly-Tyr with nitrite at pH 4 to 5, where NO2. is formed by acid decomposition of HONO. It is recalled in this context that NO2.-induced oxidations, by regenerating NO2-, can propagate NO2./NO2- redox cycling under acidic conditions. Even faster than with tyrosine is the NO2.-induced oxidation of cysteine-thiolate (k9 = 2.4 X 10(8) M-1 S-1 at pH 9.2), involving the transient formation of cystinyl radical anions. The interaction of NO2. with Gly-Trp was comparably slow (k approximately 10(6) M-1 S-1), and no reaction was detectable by pulse radiolysis with Met-Gly and (Cys-Gly)2, or with DNA. Slow reactions of NO2. were observed with arachidonic acid (k approximately 10(6) M-1 S-1 at pH 9.0) and with linoleate (k approximately 2 X 10(5) M-1 S-1 at pH 9.4), indicating that NO2. is capable of initiating lipid peroxidation even in an aqueous environment. NO2.-Induced tyrosine nitration, using 50 microM Gly-Tyr at pH 8.2, was hardly inhibited, however, in the presence of 1 mM linoleate, and was not affected at all in the presence of 5 mM dimethylamine (a nitrosamine precursor). It is concluded that protein modifications, and particularly phenol and thiol oxidation, may be an important mechanism, as well as initiation of lipid peroxidation, of action of NO2. in biological systems.

Chemical Phenomena↗
PubMed1986

Purification and partial sequence of the Mr 10,000 phosphoprotein from spinach thylakoids.

The Mr 10,000 phosphoprotein was purified from photosystem II particles by solubilization of the particles in 5% (w/v) dodecyl dimethylamine oxide, centrifugation in 10% (w/v) sucrose, and three chromatography steps. The purified phosphoprotein showed a unique NH2 terminus indicating a highly purified polypeptide. The amino acid sequence for the first nine residues is NH2-Ala-Thr-Gln-Thr-Val-Glu-Ser-Ser-Ser . . . COOH. The amino acid composition was determined and could also be used to help distinguish the polypeptide from other known thylakoid proteins. The sequence and composition data indicated that the Mr 10,000 phosphoprotein is neither the hydrophobic 8-kDa subunit of the energy coupling complex nor cytochrome b-559, but rather a unique, as yet unidentified, polypeptide associated with photosystem II.

Amino Acid Sequence↗
PubMed1992

Betaine:homocysteine methyltransferase from rat liver: purification and inhibition by a boronic acid substrate analog.

Betaine:homocysteine methyltransferase (BHMT) from rat liver has been highly purified by an efficient procedure requiring only two chromatographic steps: Sephadex G-100 chromatography and fast protein liquid chromatography chromatofocusing. A 170-fold purification and 7.5% overall yield were achieved. Chromatofocusing yielded three active forms of BHMT with pI values near 8.0, 7.6, and 7.0. The subunit molecular weight of each active form is 45,000 Da as determined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, and the native enzyme has a molecular weight of 270,000 as determined by exclusion chromatography. The stability of the purified enzyme was found to be potentiated by the presence of 1 mM dimethylglycine and 1 mM homocysteine. Boronate analogs of betaine (pinanyl N,N,N-trimethylaminomethaneboronate) (4) and dimethylglycine (pinanyl N,N-dimethylaminomethaneboronate) were synthesized from pinanyl iodomethaneboronate (3) and trimethylamine or dimethylamine, respectively. The free acid of the betaine analog (5) was reversibly generated from (4). The inhibition of BHMT by (5) appears competitive with a Ki = 45 microM. Since the Km for betaine measured with the purified enzyme is near 0.1 mM, the boronic acid analog of betaine appears to function effectively as a substrate analog inhibitor of BHMT. The analog does not appear to act as a methyl donor to homocysteine when (5) is substituted for betaine in the enzyme reaction. In addition, an enzyme assay based upon C3-cyano reverse phase HPLC detection of the o-phthalaldehyde derivative of methionine was developed as an alternative to the standard radiochemical assay. Betaine:homocysteine methyltransferase in the picomole range can be quantitated using this assay as indicated by a linear response of enzyme activity to protein concentration.

Animals↗
PubMed1979

Photooxidation of the cytochrome b-559 in the presence of various substituted 2-anilinothiophenes and of some other compounds, in Chlamydomonas reinhardtii.

Five substituted 2-anilinothiophenes and two substituted carbonylcyanide-phenylhydrazones were comparatively studied with respect to their capacities for inducing photooxidation of the cytochrome b-559 in chloroplast fragments and in whole cells of Chlamydomonas reinhardtii (wild type and P-700-lacking mutant Fl 5). In addition, some other compounds: antimycin A, picric acid, tetraphenylboron and NH4Cl were also tested. Cytochrome b-559 photooxidations were clearly observed in the presence of 2-(3-chloro-4-trifluoromethyl)anilino-3,5-dinitrothiophene (ANT 2p), 2-(3,4,5-trichloro)anilino-3,5-dinitrothiophene (ANT 2s), 2-(4-chloro)anilino-3,5-dinitrothiophene and, with greater amplitudes, in the presence of carbonylcyanide-p-trifluoromethoxyphenylhydrazone and carbonylcyanide-m-chlorophenylhydrazone, both in whole cells and in chloroplast fragments. Picric acid, antimycin A and tetraphenylboron were also able to induce cytochrome b-559 photooxidation in chloroplast fragments, but not in whole cells. In the wild type, the highest photoinduced redox changes were 1.1 (carbonylcyanide-p-trifluoromethoxyphenylhydrazone, carbonylcyanide-m-chlorophenyl-hydrazone) and 0.6 (ANT 2p, ANT 2s) mumol of oxidized cytochrome b-559/1 mmol of chlorophyll, corresponding to 40% and 23% of the redox changes which could be induced chemically. All these cytochrome b-559 photooxidations, the greater part of which was inhibited by 3-(3,4-dichloropheny)-1,1-dimethylurea and occurred in the mutant Fl 5, appeared to be mainly Photosystem II-dependent reactions. But 3-(3,4-dichlorophenyl)-1,1-dimethylurea-insensitive Photosystem I-dependent photooxidations of cytochrome b-559 occurred also in the wild type. On the other hand, 2-(4-dimethylamine)-anilino-3,5-dinitrothiophene, 2-N-methyl-(3-chloro-4-trifluoromethyl)anilino-3,5-dinitrothiophene and NH4Cl did not induce any cytochrome b-559 photooxidation. These results were discussed taking in consideration the nature of the molecular substitutions of the various tested substances and their respective acceleration of the deactivation reactions of the water-splitting enzyme system Y of photosynthesis capacities which had been defined elsewhere by Renger (Renger, G. (1972) Biochim. Biophys. Acta 256, 428-439) for spinach chloroplasts. Like the acceleration of the deactivation reactions of the water-splitting enzyme system Y effect, the capacity for inducing the cytochrome b-559 photooxidation appeared dependent on the acidity of the NH group and on the number of halogenous substituents in the aromatic ring of the molecule. The greatest action towards cytochrome b-559 photooxidation was obtained with the most active acceleration of the deactivation reactions of the water-splitting enzyme system Y agents: carbonylcyanide-p-trifluoromethoxyphenylhydrazone, ANT 2p and ANT 2s.

Aniline Compounds↗
PubMed1984

Dimethylnitrosamine inhibits the glucagon-stimulated adenylate cyclase activity of rat liver plasma membranes and decreases plasma membrane fluidity.

The effect of the hepatocarcinogen dimethylnitrosamine on rat liver plasma membrane adenylate cyclase activity and lipid fluidity was assessed. Glucagon-stimulated adenylate cyclase activity exhibited a complex response to increasing concentrations of dimethylnitrosamine, whereas fluoride-stimulated adenylate cyclase activity was progressively inhibited. Maximal inhibitory effects were observed at a concentration of 15 mM in both cases. The activity of detergent-solubilized adenylate cyclase was unaffected by dimethylnitrosamine. ESR analysis using a fatty acid spin probe showed that dimethylnitrosamine produced a marked, dose-dependent reduction in the fluidity of the plasma membrane with a maximal effect occurring at 20 mM. Dimethylnitrosamine also elevated the temperature at which the lipid phase separation occurred in rat liver plasma membranes, from 28 degrees C to 31 degrees C. The non-carcinogenic but structurally similar compound, dimethylamine hydrochloride neither inhibited adenylate cyclase nor decreased plasma membrane fluidity. It is suggested that the decrease in membrane fluidity, induced by dimethylnitrosamine, via its effects on membrane fluidity, could influence plasma membrane function and cellular regulation.

Adenylyl Cyclases↗
PubMed1995

Interaction of sphingomyelinase with sphingomyelin analogs modified at the C-1 and C-3 positions of the sphingosine backbone.

In this study, analogs differing at the C-1 or C-3 position of the sphingosine backbone of sphingomyelin were examined in neutral pH-optimum sphingomyelinase assays. Two analogs modified at the C-1 position, ceramide-1-phosphate and ceramide-1-phosphoethanol-N,N-dimethylamine, could act as modest substrates but showed no ability to inhibit the reaction when egg sphingomyelin was used as the substrate. Four analogs of sphingomyelin differing at the C-3 position were used in which the hydroxyl group was replaced by a hydrogen atom (to give a deoxy-sphingomyelin analog), or with a O-methyl, O-ethyl or O-tetrahydropyranyl group. The deoxy analog showed no ability to compete with substrate of sphingomyelinase nor could it be hydrolyzed by the enzyme, suggesting that the hydroxyl group is a required substituent for the substrate. The 3-O-methyl and 3-O-ethyl-sphingomyelin analogs were inhibitors, with IC50 values of 50 microM and 140 microM, respectively at standard assay conditions. However, when the rat brain acidic pH-optimum sphingomyelinase was used, no inhibition by the 3-O-methyl analog could be detected. The size of the alkyl group on the ether moiety was important, as shown by the inability of 3-O-tetrahydropyranyl-sphingomyelin to compete with substrate of neutral pH-optimum sphingomyelinase.

Alkylation↗
PubMed1996

Quaternary nitrogen compounds affect carnitine distribution in rats. Particular emphasis on edrophonium.

Edrophonium (ethyl(m-hydroxyphenyl)dimethylamine) acutely modifies carnitine levels in different rat tissues, increasing hepatic and reducing blood and renal levels. After 2 h edrophonium treatment, the total serum carnitine levels were decreased by 16 (P < 0.001) and 33 (P < 0.001) percent in fed and fasted rats respectively compared to control, and in kidney the levels decreased by 11 (P < 0.05) and 34 (P < 0.001) percent whereas in liver the edrophonium treatment increased the levels by 43 (P < 0.001) and 59 (P < 0.001) percent. The edrophonium action does not depend on the route of administration or on the nutritional state of the animal. Its activity on carnitine levels is neither accompanied by significant variation of serum parameters of carbohydrate, fat and protein metabolism nor of insulin levels. The edrophonium activity is not related to cholinergic action, as physostigmine and ambenonium at concentrations known to increase cholinergic activity do not modify carnitine distribution in tissues. Trimethylphenylammonium (TPA) and trimethyl(p-aminophenyl)ammonium (TPA.NH2), compounds structurally similar to edrophonium, are on the contrary active on levels of carnitine and this effect is not related to their cholinergic potency. In 24 h fasted rats after the TPA and TPA. NH2 treatment, the total serum carnitine levels were decreased by 32 (P < 0.001) and 13 (n.s.) percent respectively compared to control, and in kidney the levels decreased by 15 (P < 0.02) and 5 (n.s.) percent, whereas in liver the treatment increased the levels by 72 (P < 0.001) and 45 (P < 0.01) percent. Moreover atropine, an acetylcholine antagonist, affects carnitine distribution in a way similar to edrophonium. Edrophonium activity on carnitine distribution, probably affects (inter)cellular carnitine transport by direct action on plasma membrane. Effect on capillary endothelium may be responsible for its observed action on muscle contraction force in imminent ischemia.

Ambenonium Chloride↗
PubMed1987

Occurrence of a new enzyme catalyzing the direct conversion of NG,NG-dimethyl-L-arginine to L-citrulline in rats.

An enzyme concerned with the degradation of NG,NG-dimethyl-L-arginine to L-citrulline was investigated in rats. The enzyme purified from rat kidney catalyzed the direct conversion of NG,NG-dimethyl-L-arginine to L-citrulline with liberation of dimethylamine from the methylated guanidino moiety. The reaction required no co-factor and the maximum activity was obtained at pH 6.5. The enzyme was highly specific for NG,NG-dimethyl-L-arginine.

Amidohydrolases↗
PubMed1982

The effects of nitrogen mustard (HN2) on activities of the plasma membrane of PC6A mouse plasmacytoma cells.

Nitrogen mustard, HN2 (10(-5) M), inhibited the transport of the potassium congener 86rubidium into PC6A mouse plasmacytoma cells by 45% after a 4 hr incubation at 37 degree in vitro. HN2 (10(-3) M) had a rapid effect on the profile of 86rubidium transport into PC6A cells when added simultaneously with the 86rubidium whereas a monofunctional analogue of HN2((2-chloroethyl)dimethylamine) had no effect at 10(-3) M. The transport of the amino acid analogues alpha-aminoisobutyric acid and cycloleucine into PC6A cells was inhibited by 19% and 5% respectively after a 4 hr incubation with 10(-5) M HN2. The results suggest that the activity of plasma membrane Na+K+-ATPase may be affected by HN2. This enzyme may play a pivotal role in controlling cell growth and division. Crude cell membrane preparations from PC6A cells had variable Na+K+-ATPase activity which was possibly due to contamination with mitochondrial Mg2+-ATPase. Incubation of a crude cell membrane preparation in the presence of 40 nM dicyclohexylcarbodiimide gave constant Na+K+-ATPase activity which was inhibited by 44% on incubation with HN2 (10(-3) M) for 0.5 hr. The monofunctional analogue of HN2 inhibited this preparation by only 7% under the same conditions. It is suggested that inhibition of Na+K+-ATPase by HN2 may be an important facet of its cytotoxic activity.

Adenosine Triphosphatases↗
PubMed1984

Radical formation during autoxidation of 4-dimethylaminophenol and some properties of the reaction products.

4-Dimethylaminophenol (DMAP), after intravenous injection, rapidly forms ferrihaemoglobin and has been successfully used in the treatment of cyanide poisoning. Since DMAP produces many equivalents of ferrihaemoglobin, it was of interest to obtain further insight into this catalytic process. DMAP autoxidizes readily at pH regions above neutrality, a process which is markedly accelerated by oxyhaemoglobin. The resulting red-coloured product was identified as the 4-(N,N-dimethylamino) phenoxyl radical by EPR spectroscopy. The same radical was also produced by pulse radiolysis and oxidation with ferricyanide. The 4-(N,N-dimethylamino)phenoxyl radical is quite unstable and decays in a pseudo-first order reaction (k = 0.4 sec-1 at pH 8.5, 22 degrees) with the formation of p-benzoquinone and dimethylamine. This observed decay rate is identical with the rate of hydrolysis of N,N-dimethylquinonimine. When a solution containing the phenoxyl radical was extracted with ether, half the stoichiometric amount of DMAP was recovered. Hence it is apparent that the phenoxyl radical decays by disproportionation yielding DMAP and N,N-dimethylquinonimine. The latter product then quickly hydrolyses. The equilibrium of this disproportionation reaction is far towards the radical side, and the pseudo-first order hydrolysis controls the radical decay rate. p-Benzoquinone rapidly reacts with DMAP (k2 = 2 X 10(4) M-1 sec-1) with the formation of the 4-(N,N-dimethylamino)phenoxyl and the semiquinone radicals. This reaction explains the autocatalytic phenoxyl radical formation during autoxidation of DMAP. DMAP is not oxidized by H2O2 or O-.2 but the 4-(N,N-dimethylamino)phenoxyl radical is very rapidly reduced by O-.2 (k2 = 2 X 10(8) M-1 sec-1). In addition, the phenoxyl radical is quickly reduced by NAD(P)H or GSH with the formation of NAD(P)+ or GSSG. Since DMAP is also able to reduce two equivalents of ferrihaemoglobin (provided that the ferrohaemoglobin produced is trapped by carbon monoxide), electrophilic addition reactions of the phenoxyl radical seem unimportant in contrast to N,N-dimethylquinonimine. Hence, during the catalytic ferrihaemoglobin formation, DMAP is oxidized by oxygen which is activated by haemoglobin, and the phenoxyl radical oxidizes ferrohaemoglobin. This catalytic process is terminated by covalent binding of N,N-dimethylquinonimine to SH groups of haemoglobin (and GSH in red cells).

Aminophenols↗