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At least 19 recordsLinked to original sources
PubMed1979

Mutagenic evaluation of nitroparaffins in the Salmonella typhimurium/mammalian-microsome test and the micronucleus test.

Three nitroparaffins (nitroethane, 1-nitropropane, and 2-nitropropane) were studied in the Salmonella typhimurium/mammalian microsome (Ames) test, with and without microsomal activation systems. Nitroethane and 2-nitropropane also were studied in an in vivo mutagenic (micronucleus) test. These studies were undertaken because these solvents are widely used in the chemical and pharmaceutical industries and 2-nitropropane was reported to cause liver cancer in rats exposed by the inhalation route. Neither nitroethane nor 1-nitropropane was active in the Ames test with Salmonella tester-strains TA1537, TA92, TA98, or TA100. However, 2-nitropropane produced a significant increase in revertants in all of these tester strains, particularly strain TA100, where 3 microliter/plate doubled the number of revertants in the presence of microsomal enzymes. Negative results were obtained with both nitroethane and 2-nitropropane in micronucleus tests. These studies have shown that 2-nitropropane has the potential for causing point mutations in a microbial test system. However, this compound probably will not cause a chromosome mutation of the clastogenic type.

Alkanes↗
PubMed2001

Evaluation of the TOPKAT system for predicting the carcinogenicity of chemicals.

The TOPKAT computer-based system for predicting chemical carcinogens was evaluated by determining its ability to predict the carcinogenicity of chemicals tested by the National Toxicology Program. TOPKAT was not effective in identifying potential rodent carcinogens and noncarcinogens in the data set analyzed. The chemicals in the TOPKAT database of known carcinogens and noncarcinogens that the software identifies as most "similar" to unknown chemicals are illustrated using six examples. These "similar" chemicals generally bear no apparent relationship to the chemical of interest with regard to metabolism or potential mechanism of carcinogenicity. Environ. Mol. Mutagen. 37:55-69, 2001 Published 2001 Wiley-Liss, Inc.

Animals↗
PubMed1986

Cytochrome P-450-mediated denitrification of 2-nitropropane in mouse liver microsomes.

Enzymatic denitrification of 2-nitropropane (2NP) was investigated in an NADPH-dependent hepatic microsomal system from male CD1 mice. The involvement of cytochrome P-450 (P-450) as the catalyst in 2NP denitrification was revealed by the induction of nitrite-releasing activity following phenobarbital (PB) pretreatment, by a decrease in activity with carbon tetrachloride pretreatment, by the inhibition of the reaction with classical P-450 inhibitors, and by the observation of a type I binding spectrum. Under optimal conditions, two pH-dependent peaks of activity were observed at pH 7.6 and pH 8.8, each with its own optimal substrate concentration. Inhibition of the reaction by metyrapone and carbon monoxide (CO) (among others) produced differential responses dependent on pH. These results, along with two pH optima and two substrate optima, suggested the involvement of multiple P-450 isozymes. Average specific activities were 8.05 nmoles of nitrite released per minute per milligram microsomal protein at pH 7.6 and 6.44 nmoles of nitrite released per minute per milligram microsomal protein at pH 8.8. Acetone was identified as the second product of the reaction by gas chromatography/mass spectrometry (GC/MS). Stoichiometry studies indicated that the acetone production was slightly less than expected (about 70%) from nitrite release. Up to 25% residual activity was observed under anaerobic conditions. These results suggested that though the predominant reaction mechanism was oxidative, oxygen-independent metabolism of 2NP also occurred to some extent. In contrast to the reported lack of activity in untreated rat, the observed denitrification in uninduced mouse liver microsomes was significant and suggested that major species-specific differences exist in the in vitro metabolism of 2NP.

Aerobiosis↗
PubMed1995

Inhibition of aldose reductase: 13C NMR studies in isolated peripheral nerve.

We report 13C NMR measurements of the flux through aldose reductase in isolated rat sciatic nerve, and its inhibition by an aldose reductase inhibitor of the sulphonylnitromethane class. [1-13C] galactose was used as substrate, and the rate of production of [1-13C] dulcitol was measured. Quantitation required the use both of internal extracellular, and external, standards. The mean net forward flux (+/- SD) was 20 +/- 11 nmol/(mL nerve water)/min (n = 10). In the presence of the inhibitor, flux was reduced significantly (p < 0.001) to 13% of control. Since dulcitol is symmetrical, an estimate of the backward flux, to [6-13C] galactose, is also possible; under our conditions, this was negligible.

Aldehyde Reductase↗
PubMed1992

The accessibility of etheno-nucleotides to collisional quenchers and the nucleotide cleft in G- and F-actin.

Recent publication of the atomic structure of G-actin (Kabsch, W., Mannherz, H. G., Suck, D., Pai, E. F., & Holmes, K. C., 1990, Nature 347, 37-44) raises questions about how the conformation of actin changes upon its polymerization. In this work, the effects of various quenchers of etheno-nucleotides bound to G- and F-actin were examined in order to assess polymerization-related changes in the nucleotide phosphate site. The Mg(2+)-induced polymerization of actin quenched the fluorescence of the etheno-nucleotides by approximately 20% simultaneously with the increase in light scattering by actin. A conformational change at the nucleotide binding site was also indicated by greater accessibility of F-actin than G-actin to positively, negatively, and neutrally charged collisional quenchers. The difference in accessibility between G- and F-actin was greatest for I-, indicating that the environment of the etheno group is more positively charged in the polymerized form of actin. Based on calculations of the change in electric potential of the environment of the etheno group, specific polymerization-related movements of charged residues in the atomic structure of G-actin are suggested. The binding of S-1 to epsilon-ATP-G-actin increased the accessibility of the etheno group to I- even over that in Mg(2+)-polymerized actin. The quenching of the etheno group by nitromethane was, however, unaffected by the binding of S-1 to actin. Thus, the binding of S-1 induces conformational changes in the cleft region of actin that are different from those caused by Mg2+ polymerization of actin.(ABSTRACT TRUNCATED AT 250 WORDS)

Actins↗
PubMed2000

Analysis of nitrite/nitrate in biological fluids: denitrification of 2-nitropropane in F344 rats.

2-Nitropropane (2-NP), a rat hepatocarcinogen, is denitrified to nitrite and acetone by rat liver microsomes; the denitrification rate is increased using microsomes from phenobarbital (PB)-pretreated rats. To obtain evidence that denitrification of 2-NP also occurs in vivo, we attempted to determine nitrite and nitrate levels in blood sera and urines of 2-NP-treated (1.5 mmol/kg, ip, once) rats with and without PB pretreatment (80 mg/kg, ip, once daily, 3 days), using enzymatic reduction followed by the standard Griess reaction. However, due to various interfering factors, including pigment from methemoglobinemia, we found the assay had to be modified as follows: (a) reduction of nitrate to nitrite was accomplished using NADPH and nitrate reductase, (b) excess NADPH, proteins, and interfering pigments were precipitated using zinc acetate and Na(2)CO(3), and (c) the Griess reagents were prepared in 3 N HCl rather than 5% H(3)PO(4). With these modifications it became possible to show that 2-NP is indeed metabolized to nitrite in vivo and that the metabolism is increased by PB pretreatment. Two hours after 2-NP administration, rat blood serum nitrate plus nitrite levels were approximately 1600 microM (PB-pretreated) and 940 microM (vehicle-pretreated controls). The PB-pretreated and control rats, respectively, excreted 250 and 120 micromol nitrate/nitrite in the 24-h urine post 2-NP treatment. The modifications described make the method more specific, reproducible, and more widely applicable.

Animals↗
PubMed2000

Formation of iron(II)-nitrosoalkane complexes: a new activity of microperoxidase 8.

Microperoxidase 8 (MP8) is a heme octapeptide, obtained by enzymatic hydrolysis of heart cytochrome c, in which a histidine is axially coordinated to the heme iron, and acts as its fifth ligand. It exhibits two kinds of activities: a peroxidase-like activity and a cytochrome P450-like activity. We here show that MP8 is not only able to oxidize various aliphatic and aromatic hydroxylamines with the formation of MP8-Fe(II)-nitrosoalkane or -arene complexes absorbing around 414 nm, but also that these complexes can be obtained by reduction of nitroalkanes. This is the first example of fully characterized iron(II)-metabolite complexes of MP8. Such complexes constitute good models for those obtained upon oxidation of amphetamine or macrolids by cytochromes P450. In addition, this is a new catalytic activity of MP8, which validates the use of this mini-enzyme as a convenient model for hemoproteins of interest in toxicology and pharmacology such as cytochromes P450 and peroxidases.

Alkanes↗
PubMed1996

Chronic inhalation exposure of rats to nitromethane.

Male and female Long-Evans rats were housed in inhalation chambers and exposed to vapors of nitromethane (NM) at either 100 or 200 ppm. The animals were exposed 7 hr per day, 5 days per week for 2 years. Control groups of rats were also housed in a similar inhalation chamber, but NM was not introduced into the chamber. The animals were observed daily for signs of pharmacologic or toxicologic effect and body weights were recorded periodically. At the 2-year termination of the exposure period, clinical laboratory examinations (serum chemistry and hematology) were performed on selected animals and all surviving animals were sacrificed. All animals were necropsied and subjected to a thorough histopathologic examination. During the study there were no pharmacologic effects from exposure to NM at either 100 or 200 ppm. There was no effect on mortality on either sex at either exposure level. Body weights of male rats exposed to NM were not significantly different from those of control rats, but the body weights of female rats of both exposure groups were slightly less than their controls. There was no effect of exposure of rats of either sex to either level of NM on hematology. There were no clinically significant effects on serum chemistry. There were no effects of exposure to NM on organ weights. There were no significant differences in the nonneoplastic or neoplastic pathology related to exposure to NM.

Administration, Inhalation↗
PubMed1993

Inhibition of aldose reductase by (2,6-dimethylphenylsulphonyl)nitromethane: possible implications for the nature of an inhibitor binding site and a cause of biphasic kinetics.

Aldose reductase (aldehyde reductase 2, ALR2) is often isolated as a mixture of two forms which are sensitive (ALR2S), or insensitive (ALR2I), to inhibitors. We show that ICI 215918 ((2-6-dimethylphenylsulphonyl)-nitromethane) follows either noncompetitive, or uncompetitive kinetics with respect to aldehyde for ALR2S, or the closely related enzyme, aldehyde reductase (aldehyde reductase 1, ALR1). Similar behaviour is exhibited by two other structural types of aldose reductase inhibitor (ARI), spirohydantoins and acetic acids, when either aldehyde, or NADPH is varied. For ALR2S, we have demonstrated kinetic competition between a sulphonylnitromethane, an acetic acid and a spirohydantoin. Thus, different ARIs probably have overlapping binding sites. Published studies imply that ALR2 follows an ordered mechanism where coenzyme binds first and induces a reversible conformation change (E.NADPH-->E*.NADPH). Reduction of aldehyde appears rate-limited by the step E*.NADP+-->E.NADP+. Spontaneous activation converts ALR2S into ALR2I and increases kcat. This must be associated with acceleration of the rate-determining step. We now propose the following hypothesis to explain characteristics of ARIs. (1) Inhibitors preferentially bind to the E* conformation. (2) The ARI binding site contains residues in common with that for aldehyde substrates. When aldehyde is varied, uncompetitive inhibition arises from association at the site for alcohol product in the E*.NADP+ complex which has little affinity for the substrate. Any competitive inhibition arises from use of the aldehyde site in the E*.NADPH complex. (3) Acceleration of the E*.NADP+-->E.NADP+ step upon activation of ALR2 reduces steady state levels of E* and so decreases sensitivity to ARIs.

Acetates↗
PubMed1980

Serotonin in experimental histidinemia.

An experimental histidinemia was obtained in rats by in vivo administration of nitromethane, a histidase inhibitor. The magnitude of increase in plasma histidine in the nitromethane-treated rats was in the same range as that in the histidinemic subjects. No modifications were observed in the serotonin concentrations in blood or in various areas of brain between the nitromethane-treated rats and the control rats. No dramatic modifications of serotonin metabolism seem to be implicated in histidinemia, unlike phenylketonuria.

Amino Acid Metabolism, Inborn Errors↗
PubMed1990

Dose-dependent emergence of preneoplastic foci in rat livers after exposure to 2-nitropropane.

Male and female Sprague-Dawley rats, 4-6 days old were exposed for 3 weeks (6 h/day, 5 days/week) to 2-nitropropane vapours of 0, 25, 40, 50, 80 and 125 ppm. One week later polychlorinated biphenyls (Clophen A50, 10 mg/kg body weight) were administered for promotion twice a week for 8 weeks. Thirteen weeks after starting the experiments the logarithms of the numbers of preneoplastic liver foci deficient in adenosine-5'-triphosphatase were found to be linearly related to the exposure concentrations of 2-nitropropane. Male rats exhibited an approximately four times lower foci incidence than females.

Adenosine Triphosphatases↗
PubMed1999

Effect of complex polyphenols and tannins from red wine (WCPT) on chemically induced oxidative DNA damage in the rat.

BACKGROUND: Flavonoids are polyphenolic antioxidants occurring in vegetables and fruits as well as beverages such as tea and wine which have been thought to influence oxidative damage. AIM OF THE STUDY: We wanted to verify whether a complex mixture of wine tannins (wine complex polyphenols and tannins, WCPT) prevent chemically-induced oxidative DNA damage in vivo. METHODS: Oxidative DNA damage was evaluated by measuring the ratio of 8-hydroxy-2'-deoxyguanosine (80HdG)/ 2-deoxyguanosine (2dG) x 10(-6) in hydrolyzed DNA using HPLC coupled with electrochemical and UV detectors. RESULTS: We treated rats with WCPT (57 mg/kg p.o.) for 14 d, a dose 10-fold higher than what a moderate wine drinker would be exposed to. WCPT administration significantly reduced the ratio of 80HdG/2dG x 10(-6) in liver DNA obtained from rats treated with 2-nitropropane (2NP) relative to controls administered 2NP only (33. 3 +/- 2.5 vs. 44.9 +/- 3.2 x 10(-6) 2dG; micro +/- SE; p<0.05). On the contrary, pretreatment with WCPT for 10 d did not protect the colon mucosa from oxidative DNA damage induced by 1, 2-dimethylhydrazine (DMH). 2NP and DMH are hepatic and colon carcinogens, respectively, capable of inducing oxidative DNA damage. CONCLUSIONS: WCPT have protective action against some types of chemically-induced oxidative DNA damage in vivo.

1,2-Dimethylhydrazine↗