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PubMed1997

Assessment of the developmental toxicity, metabolism, and placental transfer of N,N-dimethylformamide administered to pregnant rats.

This study evaluates the developmental toxicity and placental and milk transfer of N,N-dimethylformamide (DMF) in rats. Sprague-Dawley rats were given 0, 50, 100, 200, and 300 mg DMF/kg/day, by gavage, on Gestational Days (GD) 6 through 20. Maternal toxicity was indicated by depressions in weight gain and food consumption at doses >/=100 mg/kg. Fetal toxicity was indicated by decreased fetal body weight at doses >/=100 mg/kg, and by increased incidences of two skeletal variations (absent or poorly ossified supraoccipital and sternebrae) at 200 and 300 mg/kg. Thus, the maternal and developmental no-observed-adverse-effect level was 50 mg/kg/day. The time course disposition of [14C]DMF was examined over a 48-hr period in GD12- and GD18-pregnant rats after a single oral dose of 100 mg [14C]DMF/kg. Peak concentrations of radiocarbon occurred within 1 hr after dosing. Embryonic (GD12) and fetal (GD18) tissues accounted for 0.15 and 6% of the administered dose, respectively. Levels of radiocarbon in embryonic and fetal tissues were equal or slightly less than in maternal plasma up to 8 and 24 hr, respectively, and higher thereafter. HPLC analysis performed at intervals from 1 to 8 hr on GD12 and 1-24 hr on GD18 indicated that unchanged DMF and metabolites were readily transferred to the embryonic and fetal tissues, where their levels were generally equal to those in maternal plasma. The parent compound accounted for most of the radioactivity until 4-8 hr and then decreased. N-Hydroxymethyl-N-methylformamide (HMMF) and N-methylformamide (NMF) were the predominent metabolites and increased with time. Much lower concentrations were found for formamide and N-acetyl-S-(N-methylcarbamoyl)cysteine. Transfer of radioactivity into milk was studied in dams given a single oral administration of 100 mg [14C]DMF on Lactation Day 14. DMF, HMMF, and NMF were found in the milk at concentrations equal to those in plasma.

Abnormalities, Drug-Induced↗
PubMed1987

N-methyl antitumour agents. A distinct class of anticancer drugs?

This article reviews the structure-activity characteristics, mode of action, pharmacokinetics and clinical utility of a group of chemically dissimilar antitumour agents which have as a common structural feature the N-methyl moiety. The importance of this feature is shown by the fact that molecules without a substituent on the nitrogen or compounds with N-alkyl groups other than methyl are usually inactive in experimental systems. This observation is supported by structure-activity studies with N-alkyl derivatives of s-triazines, triazenes, formamides, hydrazines and nitrosoureas. Representatives of these structural types which have found clinical application are, respectively, hexamethylmelamine, dacarbazine, N-methylformamide, procarbazine and streptozotocin. Mode of action studies have shown that dacarbazine, procarbazine and streptozotocin can give rise to species capable of methylating nucleic acid. This may be the lesion which produces antitumour activity. The mechanism of action of N-methylmelamines and N-methylformamide remains unclear. There is good evidence that, with the exception of N-methylnitrosoureas, host metabolism is prerequisite for activity with these agents. Although not pronounced, the clinical activity of N-methyl antitumour agents is useful, particularly as activity is not associated with severe haematological toxicity. Furthermore, responses may be observed in patients resistant to bifunctional alkylating agents. It is concluded that the drugs reviewed herein show a degree of coincidence in terms of their biological properties which may warrant a common classification. The term N-methyl antitumour agent is proposed.

Alkylating Agents↗
PubMed1977

Effect of different denaturing agents on the detectability of specific DNA sequences of various base compositions by in situ hybridisation.

In situ hybridisation of certain AT rich and GC rich satellite DNA complementary RNAs (cRNAs) to their homologous chromosomes at their respective optimal rate temperatures (TOPTS) after denaturation with various reagents (0.2 N HCl, 0.07 N NaOH, 90% formamide and heat) led to the following conclusions. -- Heat denaturation of chromosomal DNA in 0.1 X SSC at 100 degrees C gives significantly higher grain counts regardless of DNA base composition, HCl denaturation discriminates markedly against GC rich DNA. Chromosome morphology is best preserved after HCl and heat denaturation.

Animals↗
PubMed1992

Absorption, metabolism and elimination of N,N-dimethylformamide in humans.

Excretion of N,N-dimethylformamide (DMF) and DMF metabolites N-hydroxymethyl-N-methylformamide ("MF"), N-hydroxymethyl-formamide ("F") and N-acetyl-S-(N-methylcarbamoyl)cysteine (AMCC) has been monitored in the urine of volunteers during and after their 8-h exposure to DMF vapour at a concentration of 10, 30 and 60 mg.m-3. The pulmonary ventilation in these experiments was typically about 10 l.min-1 and the retention in the respiratory tract was 90%. After exposure to 30mg DMF.m-3, the yield of compound determined in the urine represented 0.3% (DMF), 22.3% ("MF"), 13.2% ("F") and 13.4% (AMCC) of the dose absorbed via the respiratory tract. The excretion curves of the particular compounds attained their maximum 6-8h (DMF), 6-8h ("MF"), 8-14h ("F") and 24-34h (AMCC) after the start of the exposure. The half-times of excretion were approximately 2, 4, 7 and 23 h respectively. In contrast to slow elimination of AMCC after exposure to DMF, AMCC was eliminated rapidly after AMCC intake. This discrepancy could be explained by rate-limiting reversible protein binding of a reactive metabolic intermediate of DMF, possibly methylisocyanate.

Absorption↗
PubMed1975

Permeability pathways for non-electrolytes through Bufo bufo gall-bladder.

Amphotericin B treatment increases the thiourea, D-xylose and mannitol fluxes and lowers those of urea, N-methyl-urea, acetamide, formamide, and N-N'-dimethyl-thiourea. The degree of flux inhibition is related to the cellular permeability of these compounds. Most probably Amphotericin B increases the permeability of all those molecules across the luminal plasma membrane, but simultaneously elicits a cellular swelling, which reduces the diffusion across the lateral plasma membranes. This effect masks the polyene effect especially for molecules showing a mainly cellular permeation pathway such as amides and lipid soluble molecules.

Acetamides↗
PubMed1993

Modes of DAPI banding and simultaneous in situ hybridization.

By controlling the degree of chromatin denaturation through formamide incubation, or by heat treatment and/or by high pH, three types of high quality 4',6-diamidino-2-phenylindole (DAPI) bands can be produced sequentially on the same set of 5-bromo-2'-deoxyuridine (BrdU)-incorporated chromosomes: first DAPI multibanding (the equivalent of Q-banding), then partial C-banding including distamycin A (DA)/DAPI banding, and finally C-banding pattern. It is assumed that the different DAPI-chromatin interactions following these treatments reflect the different chromatin structures at the chromosomal sites. Since the DAPI banding protocol is compatible with in situ hybridization, the combination of fluorescent in situ hybridization (FISH) with DAPI banding allows the simultaneous detection of signals from the DNA probes and the identification of the chromosomal band location of the probe. We demonstrate this useful application with the localization of the cystic fibrosis and Duchenne muscular dystrophy gene probes to their appropriate bands.

Cells, Cultured↗
PubMed1994

Stabilizing and destabilizing effects on plasma membrane Ca(2+)-ATPase activity.

We have examined the temperature-dependent effects of several organic compounds on the activity of the purified Ca(2+)-ATPase of erythrocytes. The monomeric enzyme was activated either by interaction with calmodulin or by oligomerization in the absence of calmodulin. Of the four homologous solute series studied including polyols, alkanols, aprotic solvents, and N-methyl derivatives of formamide and acetamide only polyols stabilized the enzyme over a broad range of concentration and temperature. Similarity of Ca(2+)-ATPase activity patterns at 25 and 37 degrees C and in the presence of glycerol is in agreement with indirect, stabilizing interactions. Glycerol also protected the Ca(2+)-ATPase from thermal denaturation at 45 degrees C. Within each homologous series, inhibitory effects increased with increasing solute concentration and with increasing structural similarity to detergents, indicating that direct destabilizing interactions are responsible for the observed inhibition. These were comparable to the destabilizing effect of urea. Oligomers were more resistant to all inhibitory solutes as compared to calmodulin-activated monomers suggesting that the nonpolar patches of the oligomerized enzyme are less accessible to solutes.

Acetamides↗
PubMed1985

Permeability of the squid giant axon to organic cations and small nonelectrolytes.

The permeability of the Na channel of squid giant axon to organic cations and small nonelectrolytes was studied. The compounds tested were guanidinium, formamidinium, and 14C-labeled urea, formamide, thiourea, and acetone. Permeability was calculated from measurements of reversal potential and influx on internally perfused, voltage clamped squid axons. The project had two objectives: (1) to determine whether different methods of measuring the permeability of organic cations yield similar values and (2) to see whether neutral analogs of the organic cations can permeate the Na channel. Our results show that the permeability ratio of sodium to a test ion depends upon the ionic composition of the solution used. This finding is consistent with the view put forward previously that the Na channel can contain more than one ion at a time. In addition, we found that the uncharged analogs of permeant cations are not measurably permeant through the Na channel, but instead probably pass through the lipid bilayer.

Acetone↗
PubMed1987

Modulation of carcinoembryonic antigen release by HT-29 colon carcinoma line in the presence of different agents.

In this study we followed the effects of various differentiating agents on the expression of carcinoembryonic antigen (CEA) released into the medium by a colon carcinoma cell line HT-29. Butyric acid 1 mM markedly increased the level of CEA (12-fold in comparison to control levels). 12-O-tetradecanoyl-phorbol-13-acetate (TPA) 50 ng/ml and 5-azacytidine 4 x 10(-6) M increased the amount of CEA, 2- and 1.5-fold respectively. On the other hand retinoic acid 10(-5) M, N methyl-formamide 1% and N,N hexamethylene bisacetamide 2.5 mM decreased CEA 2-, 4- and 3-fold respectively. Our results emphasize that various differentiating agents affect CEA levels differently. Thus changes in CEA levels appear not to be reliable as a marker of a more differentiated phenotype.

Acetamides↗
PubMed1999

Genetic interactions between Hsp90 and the Cdc2 mitotic machinery in the fission yeast Schizosaccharomyces pombe.

In Schizosaccharomyces pombe, wee1 encodes a tyrosine kinase that inhibits entry into mitosis by phophorylating Cdc2, the universal cyclin-dependent kinase (Cdk) that regulates the G2/M transition in all eukaryotic cells. A search for suppressors of the G2 arrest caused by overexpression of weel led to the isolation of a new allele of swo1 (named swo1-w1), the gene coding for chaperone Hsp90, which is required to stabilise Weel. The swo1-w1 allele carries a glycine to aspartic acid substitution at amino acid 155 that results in a partial loss of Hsp90 function. Cells bearing the swo1-w1 mutation in combination with the point mutation cdc2-33 or cdc2-M26 showed severe mitotic defects. Genetic interactions were not observed in combination with point mutations in other cdc genes, suggesting that Cdc2 specifically interacts with Hsp90. This synthetic lethal swo1-w1 cdc2-33 (or cdc2-M26) strain had normal levels of Cdc2 protein and histone H1 phosphorylation activity, indicating that Hsp90 is required to enable Cdc2 to interact with its mitotic substrates or regulators, rather than for its proper folding or stabilisation. In a wild-type background, swo1-w1 mutant cells were sensitive to temperature as well as to other stress agents, such as KCI, ethanol and formamide. Under these stressful growth conditions, the swo1-w1 cells displayed anaphase B arrest and aberrant septation patterns, indicating that a subset of proteins involved in mitosis and cytokinesis is highly dependent on chaperone Hsp90 for function.

Alleles↗
PubMed1984

Investigation of the mechanism of hepatotoxicity of N-methylformamide in mice: effects on calcium sequestration in hepatic microsomes and mitochondria and on hepatic plasma membrane potential.

N-Methylformamide is an antitumour drug with hepatotoxic properties. Three potential targets for hepatocellular toxic lesions caused by N-methylformamide were investigated: the mitochondrial and microsomal Ca2+ pumps and the functional integrity of the plasma membrane. The administration of N-methylformamide to mice caused a dramatic decrease in the ability of the liver mitochondria to sequester [45Ca2+]. This effect was dose-dependent and was not caused by dimethylformamide, N-hydroxymethylformamide or formamide. The microsomal Ca2+ pump was not affected by N-methylformamide. Incubations of isolated mitochondria with N-methylformamide for 1 hr also led to the inhibition of the Ca2+ sequestration. Incubation of isolated mouse hepatocytes with N-methylformamide did not cause changes in plasma membrane potential as measured using the lipophilic cation triphenylmethylphosphonium. Of the three targets studied, the mitochondrial Ca2+ pump may be the one through which N-methylformamide triggers the events leading ultimately to hepatic necrosis.

Animals↗
PubMed1984

An investigation of the mechanism of hepatotoxicity of the antitumour agent N-methylformamide in mice.

N-Methylformamide (NMF) has been reported to cause liver damage in animals and man. This hepatotoxicity was characterized in BALB/c mice by the release of liver enzymes into the plasma and by histopathological examination of livers after single and repeated administration of NMF. Whereas plasma levels of sorbitol dehydrogenase were elevated dramatically 24 hr after 400 mg/kg given as a single dose, the glutathione content of the livers was not different from controls even after repeated administration. Liver damage was apparent on gross inspection and was defined as periacinar necrosis on histopathology. A dose of 100 mg/kg did not cause damage even after repeated injections on five consecutive days. The hypothesis that NMF is metabolized to a chemically reactive species was tested. Incubation of mouse hepatocytes with 7 mM NMF for 80 min produced a decrease in intracellular glutathione. Exposure of hepatocytes to NMF for 240 min led to the production of breakdown products of lipid peroxides at levels significantly above controls. However, incubation of microsomes or mitochondria with NMF and NADPH did not lead to raised levels of lipid peroxides. The effects described were specific to NMF as incubation of N,N-dimethylformamide, N-hydroxymethylformamide or formamide with hepatocytes did not result in glutathione depletion or increased lipid peroxidation. NMF undergoes extensive metabolism in vivo and the results indicate that NMF forms a chemically reactive metabolite, even though incubation of the drug with liver fractions or hepatocytes did not lead to metabolites at levels which were analytically identifiable.

Animals↗
PubMed1986

Designed inhibitors of horse liver alcohol dehydrogenase. Effect of active-site metal ion substitution.

3-(p-Butoxyphenyl)propionamide, -thioamide and -hydrazide and the formamide of p-butoxybenzylamine were tested as inhibitors of cadmium(II) and cobalt(II) active-site substituted alcohol dehydrogenase. The results agree with a direct coordination of these inhibitors except for the hydrazide to the active-site metal ion, in the enzyme-NADH-inhibitor complex. The hydrazide might be situated at some distance from the metal ion without a direct coordination bond.

Alcohol Oxidoreductases↗
PubMed1990

N-furfurylformamide as a pseudo-substrate for formylmethanofuran converting enzymes from methanogenic bacteria.

Methanofuran (4-[N-(4,5,7-tricarboxyheptanoyl-gamma-L-glutamyl)-gamma-L- glutamyl)-p-(beta-aminoethyl)phenoxymethyl]-2-(aminomethyl)furan is a coenzyme involved in methanogenesis. The N-formyl derivative is an intermediate in the reduction of CO2 to CH4 and the disproportionation of methanol to CO2 and CH4. Formylmethanofuran dehydrogenase and formylmethanofuran:tetrahydromethanopterin formyltransferase are the enzymes catalyzing its conversions. We report here that the two enzymes from Methanosarcina barkeri and the formyltransferase from Methanobacterium thermoautotrophicum can also use N-furfurylformamide as a pseudo-substrate albeit with higher apparent Km and lower apparent Vmax values. N-Methylformamide, formamide, and formate were not converted indicating that the furfurylamine moiety of methanofuran is the minimum structure required for the correct binding of the coenzyme.

Aldehyde Oxidoreductases↗
PubMed1984

Oxygen affinity of bovine haemoglobin. Relevance of electrostatic and hydrophobic interactions.

We have studied the effects of organic cosolvents (monohydric alcohols and formamide) on the oxygen equilibrium of bovine haemoglobin and have compared them with the effects of the same cosolvents on the oxygen equilibrium of human haemoglobin. Our results indicate: (1) that in agreement with previous suggestions, the lower affinity of bovine haemoglobin for oxygen is not due to an increased number of salt bridges stabilizing the T structure; (2) that, following T----R transition, more hydrophobic surface is exposed to the solvent by bovine than by human haemoglobin. We suggest, therefore, that a relevant role in keeping the oxygen affinity of bovine haemoglobin lower than that of human haemoglobin is played by the higher free energy needed to expose this more hydrophobic surface to the solvent. We stress, however, that our analysis does not enable us to say which particular amino acid residues are concerned in these effects.

1-Propanol↗
PubMed1986

Effect of organic co-solvents on the dimer/tetramer equilibrium of human haemoglobin.

We have studied the effect of organic co-solvents (monohydric alcohols and formamide) on the dimer-tetramer equilibrium of human haemoglobin by measuring the dependence of oxygen affinity upon haemoglobin concentration over a 100-fold concentration range and analysing the data with a modified Monod-Wyman-Changeux model in which the equilibrium (tetramer) in equilibrium with (dimer) + (dimer) was taken into account. This procedure enabled us to obtain the dimer-tetramer equilibrium constant and to find its dependence upon co-solvent concentration. Then by following the procedure already reported for the tense----relaxed state transition of haemoglobin, we separated the co-solvent effects into bulk electrostatic and non-bulk electrostatic (hydrophobic) contributions. We believe that our results demonstrate that during haemoglobin dissociation, just as we have already shown for the tense to relaxed state transition, both charged groups and hydrophobic surfaces became exposed to the solvent.

1-Propanol↗
PubMed1986

Effects of organic co-solvents on the oxygen equilibrium of N-ethylmaleimide-treated human haemoglobin.

We have studied the effects of monohydric alcohols and formamide on the oxygen equilibrium of native and N-ethylmaleimide-treated human haemoglobin. Comparison of the results obtained for the two haemoglobins gives further and compelling evidence in favour of the model, proposed recently by our group, on the role played by the solvent in the conformational equilibria of haemoglobin; moreover the results provide direct functional evidence of the relevance of the electrostatic free energy of salt bridges to the T in equilibrium with R equilibrium of haemoglobin.

1-Propanol↗
PubMed1989

Thermodynamics of amide hydrogen bond formation in polar and apolar solvents.

We present the initial findings of a theoretical study of hydrogen bond formation between two formamide molecules in water and in carbon tetrachloride. These systems were chosen as the simplest models for secondary structure formation in the polar environment near the protein surface and the apolar environment of the protein interior. We have employed thermodynamic simulation methods to obtain absolute binding free energies and free energy profiles for the formation of peptide hydrogen bonds in the two solvents. We find that the amide hydrogen bond is stable by 8.4 kcal/mol in CCl4, and by 0.3 kcal/mol in water. Our results indicate also that the hydrogen-bonded dimer is 2.2 kcal/mol more stable in water than it is in CCl4. We compare our results with those from experiment, and discuss their use in interpreting mechanisms of protein folding.

Acetamides↗