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At least 631 records · Page 35Linked to original sources
PubMed2003

Biotransformation of hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX) by a rabbit liver cytochrome P450: insight into the mechanism of RDX biodegradation by Rhodococcus sp. strain DN22.

A unique metabolite with a molecular mass of 119 Da (C(2)H(5)N(3)O(3)) accumulated during biotransformation of hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX) by Rhodococcus sp. strain DN22 (D. Fournier, A. Halasz, J. C. Spain, P. Fiurasek, and J. Hawari, Appl. Environ. Microbiol. 68:166-172, 2002). The structure of the molecule and the reactions that led to its synthesis were not known. In the present study, we produced and purified the unknown metabolite by biotransformation of RDX with Rhodococcus sp. strain DN22 and identified the molecule as 4-nitro-2,4-diazabutanal using nuclear magnetic resonance and elemental analyses. Furthermore, we tested the hypothesis that a cytochrome P450 enzyme was responsible for RDX biotransformation by strain DN22. A cytochrome P450 2B4 from rabbit liver catalyzed a very similar biotransformation of RDX to 4-nitro-2,4-diazabutanal. Both the cytochrome P450 2B4 and intact cells of Rhodococcus sp. strain DN22 catalyzed the release of two nitrite ions from each reacted RDX molecule. A comparative study of cytochrome P450 2B4 and Rhodococcus sp. strain DN22 revealed substantial similarities in the product distribution and inhibition by cytochrome P450 inhibitors. The experimental evidence led us to propose that cytochrome P450 2B4 can catalyze two single electron transfers to RDX, thereby causing double denitration, which leads to spontaneous hydrolytic ring cleavage and decomposition to produce 4-nitro-2,4-diazabutanal. Our results provide strong evidence that a cytochrome P450 enzyme is the key enzyme responsible for RDX biotransformation by Rhodococcus sp. strain DN22.

Aerobiosis↗
PubMed2005

Mineralization of the cyclic nitramine explosive hexahydro-1,3,5-trinitro-1,3,5-triazine by Gordonia and Williamsia spp.

Hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX) is a cyclic nitroamine explosive that is a major component in many military high-explosive formulations. In this study, two aerobic bacteria that are capable of using RDX as the sole source of carbon and nitrogen to support their growth were isolated from surface soil. These bacterial strains were identified by their fatty acid profiles and 16S ribosomal gene sequences as Williamsia sp. KTR4 and Gordonia sp. KTR9. The physiology of each strain was characterized with respect to the rates of RDX degradation and [U-14C]RDX mineralization when RDX was supplied as a sole carbon and nitrogen source in the presence and absence of competing carbon and nitrogen sources. Strains KTR4 and KTR9 degraded 180 microM RDX within 72 h when RDX served as the only added carbon and nitrogen source while growing to total protein concentrations of 18.6 and 16.5 microg/ml, respectively. Mineralization of [U-14C]RDX to 14CO2 was 30% by strain KTR4 and 27% by KTR9 when RDX was the only added source of carbon and nitrogen. The addition of (NH4)2SO4- greatly inhibited KTR9's degradation of RDX but had little effect on that of KTR4. These are the first two pure bacterial cultures isolated that are able to use RDX as a sole carbon and nitrogen source. These two genera possess different physiologies with respect to RDX mineralization, and each can serve as a useful microbiological model for the study of RDX biodegradation with regard to physiology, biochemistry, and genetics.

Actinomycetales↗
PubMed2004

Use of a crop and job specific exposure matrix for estimating cumulative exposure to triazine herbicides among females in a case-control study in the Central Valley of California.

AIMS: To determine if a job exposure matrix (JEM) could be developed using the California Department of Pesticide Regulation Pesticide Usage Database in conjunction with crop, time, and county specific self reported work history and to determine if this was a feasible method to obtain exposure estimates to triazine herbicides. METHODS: Agricultural work histories were gathered from women enrolled in a population based case-control study of ovarian cancer cases and random controls. The work histories were used in conjunction with the database to construct job exposure matrices which took into account weightings for job type, work location, and crop. RESULTS: Cumulative exposure estimates were determined for 98 study subjects. Mean exposure estimates were similar for cases and controls. The exposure estimates were robust and insensitive to varying job weight assumptions. The estimates from the original weights were highly correlated with those constructed using the conservative and maximum weights. Estimates from all three schemes produced similar multivariate age adjusted odds ratios comparing cases and controls. There was a high degree of agreement in categorised quartiles of exposure between the original and conservative, and original and maximum weights. CONCLUSIONS: The exposure estimate from the JEM provides a ranking of exposure within the study population that can be utilised as an "exposure score" with which to compare groups. Although it is not an absolute exposure measurement, it does offer a substantial advance over dichotomous categories based on self report of herbicide use, particularly when subjects are unlikely to recall specific names and dates of use of herbicides.

Adolescent↗
PubMed2000

Type I nitroreductases in soil enterobacteria reduce TNT (2,4,6,-trinitrotoluene) and RDX (hexahydro-1,3,5-trinitro-1,3,5-triazine).

Many enteric bacteria express a type I oxygen-insensitive nitroreductase, which reduces nitro groups on many different nitroaromatic compounds under aerobic conditions. Enzymatic reduction of nitramines was also documented in enteric bacteria under anaerobic conditions. This study indicates that nitramine reduction in enteric bacteria is carried out by the type I, or oxygen-insensitive nitroreductase, rather than a type II enzyme. The enteric bacterium Morganella morganii strain B2 with documented hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX) nitroreductase activity, and Enterobacter cloacae strain 96-3 with documented 2,4,6-trinitrotoluene (TNT) nitroreductase activity, were used here to show that the explosives TNT and RDX were both reduced by a type I nitroreductase. Morganella morganii and E. cloacae exhibited RDX and TNT nitroreductase activities in whole cell assays. Type I nitroreductase, purified from E. cloacae, oxidized NADPH with TNT or RDX as substrate. When expression of the E. cloacae type I nitroreductase gene was induced in an Escherichia coli strain carrying a plasmid, a simultaneous increase in TNT and RDX nitroreductase activities was observed. In addition, neither TNT nor RDX nitroreductase activity was detected in nitrofurazone-resistant mutants of M. morganii. We conclude that a type I nitroreductase present in these two enteric bacteria was responsible for the nitroreduction of both types of explosive.

Enterobacter cloacae↗
PubMed1984

Mode of action of the antiphytoviral compound 2,4-dioxohexahydro-1,3,5-triazine (5-azadihydrouracil).

The time course of inhibition of potato virus X ( PVX ) synthesis by the newly developed antiphytoviral compound 2,4- dioxohexahydro -1,3,5-triazine (DHT) was determined in mechanically inoculated leaves of Nicotiana tabacum L. cv. ' Samsun '. At the permissive temperature (22 +/- 3 degrees) DHT inhibited the synthesis of PVX almost 100% within 8 h postinoculation, after which the inhibition declined. In leaves maintained at a temperature of 5 +/- 2 degrees for 5 days, DHT inhibited PVX synthesis about 65% immediately after the shift to permissive temperature. This time course of inhibition was almost identical to that of 2-thiouracil. Uracil completely overcame the inhibition of PVX replication caused by DHT when added within 2 h after incubation of leaf disks with DHT. These results indicate that DHT acts as an analogue of the pyrimidine base uracil.

Antiviral Agents↗
PubMed1979

[Carcinogenic effect of the 3-di-(hydroxymethyl-)amino-6-(5-nitro-2-furylethenyl-)1,2,4-triazines in Panfuran-S on mice].

The carcinogenic activity of Panfuran-S containing 3-di-(hydroxymethyl-)amino-6-(5-nitro-2-furylethenyl-)1,2,4-triazine (DHNT) orally administered to mice for 35 weeks was studied. DHNT produced malignant tumors of the forestomach in the highest incidence and also, in decreasing order of frequency, of the duodenum and/or jejunum, esophagus and urinary bladder. Forestomach squamous cell carcinomas were produced dose-dependently in mice receiving more than 350 ppm DHNT and rose to 100% in mice receiving 3,500 ppm. The incidence of duodenal and/or jejunal adenocarcinomas were 8 of 28 mice (29%) receiving 1,750 ppm and 10 of 17 mice (59%) receiving 3,500 ppm. The incidence of esophageal squamous cell carcinoma was 3 of 11 mice (11%) receiving 1,750 ppm and that of urinary bladder transitional cell carcinoma was 2 of 28 mice (7%) receiving 1,750 ppm and 1 of 17 mice (6%) receiving 3,500 ppm DHNT.

Animals↗
PubMed1980

Combination chemotherapy of advanced colorectal cancer with triazinate and ICRF-159 after failure of 5-Fluorouracil.

13 patients with advanced measurable colorectal cancer, having failed chemotherapy including fluorouracil, were treated on a weekly schedule with ICRF-159, 1.0 g/m2, and triazinate, 250 mg/m2. Only 1 patient had an objective partial remission, lasting 6 months. Toxicity was moderate, but acceptable. Since each of these drugs had been reported to have a 14-17% response rate in similar patient populations, the combination in the present schedule would appear to offer no benefit compared to the single agents, and cannot be recommended for further use in failure of 5-Fluorouracil therapy.

Clinical Trials as Topic↗
PubMed2006

Comparison of transcriptional responses in liver tissue and primary hepatocyte cell cultures after exposure to hexahydro-1, 3, 5-trinitro-1, 3, 5-triazine.

BACKGROUND: Cell culture systems are useful in studying toxicological effects of chemicals such as Hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX), however little is known as to how accurately isolated cells reflect responses of intact organs. In this work, we compare transcriptional responses in livers of Sprague-Dawley rats and primary hepatocyte cells after exposure to RDX to determine how faithfully the in vitro model system reflects in vivo responses. RESULTS: Expression patterns were found to be markedly different between liver tissue and primary cell cultures before exposure to RDX. Liver gene expression was enriched in processes important in toxicology such as metabolism of amino acids, lipids, aromatic compounds, and drugs when compared to cells. Transcriptional responses in cells exposed to 7.5, 15, or 30 mg/L RDX for 24 and 48 hours were different from those of livers isolated from rats 24 hours after exposure to 12, 24, or 48 mg/Kg RDX. Most of the differentially expressed genes identified across conditions and treatments could be attributed to differences between cells and tissue. Some similarity was observed in RDX effects on gene expression between tissue and cells, but also significant differences that appear to reflect the state of the cell or tissue examined. CONCLUSION: Liver tissue and primary cells express different suites of genes that suggest they have fundamental differences in their cell physiology. Expression effects related to RDX exposure in cells reflected a fraction of liver responses indicating that care must be taken in extrapolating from primary cells to whole animal organ toxicity effects.

Animals↗
PubMed1987

Phase II clinical trial of triazinate in combination with mitomycin C for patients with advanced gastric cancer.

Thirty-three patients with advanced measurable gastric cancer were treated with a combination of mitomycin C and triazinate. Twenty-nine of these patients had failed prior chemotherapy. Nine patients (27%) had an objective tumor response (median duration, 10 weeks). Median survival of all patients treated was 21 weeks. This study demonstrates that carefully selected patients with advanced gastric cancer who have failed a trial of chemotherapy, but are still ambulatory and maintaining adequate nutrition are appropriate subjects for studies of new treatment regimens. Based on the observed objective tumor response rate and median patient survival, further studies of these drugs in combination for the treatment of advanced gastric cancer are indicated.

Adenocarcinoma↗
PubMed1991

Synthesis and protective effect of 1,3,5-triazine derivatives, leukotriene C4 antagonist, on HCl.ethanol-induced gastric lesions in rats.

2,4-Diamino-[E]-6-[2-(3-pyridyl)ethenyl]-1,3,5-triazine (3a), leukotriene C4 (LTC4) antagonist, was found to possess a protective effect on HCl.ethanol-induced gastric lesions. Analogues of 3a were synthesized and evaluated for the effect as well as antagonistic activity against LTC4-induced contraction. Seven compounds (3a-d, f-h) exhibited a potent protective effect on gastric lesions which was considered to be based on the antagonistic activity against LTC4. The structure-activity relationships of the derivatives (3a-k) are discussed.

Animals↗
PubMed1992

Synthesis and aldose reductase inhibitory activity of triazine derivatives possessing acetic acid group.

N-Acetic acid derivatives of 6-aryl-pyrazolo-triazin-4-ones were synthesized for evaluation as new aldose reductase inhibitors. The intrinsic activity of each compound was assessed by measuring the inhibition of enzymatic activity in an isolated pig lens enzyme preparation. All the prepared compounds exhibited a significant in vitro aldose reductase inhibitory effect (10(-6) M less than or equal to IC50 less than or equal to 10(-4) M). Furthermore, biological activity (log 1/IC50) for most of the data sets could be correlated directly to electronic and steric parameters. Finally, spatial configuration of the most active derivative 6c (IC50 = 2 x 10(-6) M) was compared with that of tolrestat and with pharmacophor requirements of the aldose reductase inhibitor site using a molecular modeling system.

Acetates↗
PubMed1993

Syntheses of 3-substituted 1-methyl-6-phenylpyrimido[5,4-e]-1,2,4-triazine-5,7(1H,6H)-diones (6-phenyl analogs of toxoflavin) and their 4-oxides, and evaluation of antimicrobial activity of toxoflavins and their analogs.

6-Phenyl analogs of toxoflavin (1-methyl-6-phenylpyrimido[5,4-e]-1,2,4-triazine-5,7(1H,6H)-diones ) (7a--f) and their 4-oxides (8a-f) were synthesized by nitrosative or nitrative cyclization of the aldehyde hydrazones (6a-f) of 6-(1-methylhydrazino)-3-phenyluracil (5). Both sets of compounds, 7a-f and 8a-f, gave the corresponding 1-demethyl derivatives (10a-f) upon treatment with nucleophiles such as dimethylformamide (DMF) and acetic acid under heating. The activities of toxoflavins (1a-e), toxoflavin 4-oxides (3a-e) and their 6-phenyl analogs (7a-f and 8a-f) against a variety of bacterial and fungal strains were examined. Most of the compounds showed strong inhibitory activities against gram-positive bacteria. Among the compounds, 1c, 1d, 1e, and 3c exhibited the strongest inhibitions of Micrococcus lutea (0.5 micrograms/ml minimal growth-inhibitory concentration) and Staphylococcus aureus 4R (1 microgram/ml), as well as Bacillus subtilis and Staphylococcus aureus (1-2 micrograms/ml). Most of the compounds had strong antifungal activity (2-100 micrograms/ml minimal growth-inhibitory concentration) against Candida albicans and Saccharomyces cerevisiae.

Anti-Bacterial Agents↗
PubMed2002

Enantioselective effects of optically active alpha-methylbenzyl-s-triazine on the root growth of rice and Echinochloa plants and their herbicidal activity.

The chiral requirement on the alpha-methylbenzyl moiety of 2,4-diamino-6-chloro-s-triazine for sufficient inhibition of root growth was similar towards both rice and barnyard millet. With the monoalkylamino series, the most suitable configuration was markedly changed by the substituent on the other amino moiety. However, for the dialkylamino series, the (S)-enantiomer was an active inhibitor. Clear species selectivity between rice and barnyard millet was observed in the series for the (R)-enantiomers, providing high herbicidal activity toward Echinochloa plants and safety toward rice. The enantioselectivity against barnyard millet increased with increasing inhibitory activity of the active enantiomers, following Pfeiffer's rule. R-EtNH (3) controlled the growth of barnyardgrass with leaf-burning (LB) under paddy conditions, and S-EtNH (4) and S-Et2N (20) controlled the growth without LB. The RS-EtNH derivative is an interesting inhibitor controlling the growth of barnyardgrass from the just-germinated stage (by the (R)-enantiomer) to early-middle growth stage (by the (S)-enantiomer).

Echinochloa↗
PubMedDate not supplied

Comparison of an indirect format ELISA on modified graphite and polystyrene surfaces against triazines.

An indirect format enzyme-linked immuno-sorbent assay (ELISA) on graphite rods ( 0.8 mm x 20 mm) and, for comparison, on microtiter plates has been developed against terbuthylazine. For this purpose, a series of 2-aminoalkyl-4-chloro-6-terbuthyl-s-triazine-2,6-diamine ELISA haptens with alkyl spacer lengths of 2, 4, 6, and 8 CH2 groups has been synthesized. The graphite rods or the microtiter plates were covered by a polymerized glutaraldehyde network, and the ELISA haptens have been coupled by imino coupling to the free aldehyde groups of that network. epsilon-Aminocaproic acid has been used as an agent to block unspecific binding sites. The ELISA was run in a competitive mode, where the immobilized ELISA hapten and the solute terbuthylazine as a target analyte compete for the solute antibody.

Enzyme-Linked Immunosorbent Assay↗
PubMed2001

Photostabilization of butyl methoxydibenzoylmethane (Avobenzone) and ethylhexyl methoxycinnamate by bis-ethylhexyloxyphenol methoxyphenyl triazine (Tinosorb S), a new UV broadband filter.

It is now well documented that chronic UVA exposure induces damage to human skin. Therefore, modern sunscreens should not only provide protection from both UVB and UVA radiation but also maintain this protection during the entire period of exposure to the sun. UVA filters, however, are rare and not sufficiently photostable. We investigated the effect of the introduction of a new UV filter, bis-ethylhexyloxyphenol methoxyphenyl triazine (Tinosorb S), in oil in water sunscreen formulations on the photostability of butyl methoxydibenzoylmethane (Avobenzone [AVB]) after irradiation with an optically filtered Xenon arc source (UV irradiance adjusted at 1 mean effective dose [MED]/min). With spectrophotometrical methods to assess the sun protection factor (SPF) and UVA ratio and chromatographical methods to determine the amount of UV filters recovered after irradiation we showed that Tinosorb S prevented the photodegradation of AVB in a concentration-dependent way, leading to a sustained SPF and UVA ratio even after irradiation with doses of up to 30 MED. Since AVB was shown to destabilize ethylhexyl methoxycinnamate (EHM) we tested the effect of Tinosorb S in sunscreens containing this UV filter combination. Here too Tinosorb S showed photoprotective properties toward both UV filters. Thus, Tinosorb S can be used successfully to improve the photostability and efficiency of sunscreens containing AVB and EHM.

Benzoates↗
PubMed2005

Accumulation of hexahydro- 1,3,5-trinitro- 1,3,5-triazine in channel catfish (Ictalurus punctatus) and aquatic oligochaetes (Lumbriculus variegatus).

The extensively used military explosive hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX) has been widely released to the environment during production, usage, and disposal operations. Toxic effects of RDX have been reported in terrestrial and aquatic receptors, but investigations regarding the bioaccumulation potential of RDX in aquatic systems are scarce. The objective of the present study was to describe the toxicokinetics of RDX during aqueous exposure for the channel catfish (Ictalurus punctatus) and aquatic oligochaetes (Lumbriculus variegatus) and to compare the amount of RDX accumulation in juvenile catfish following aqueous exposure only, dietary exposure only, and a combination of dietary and aqueous exposure. The toxicokinetics measurements included bioconcentration factors (BCFs), uptake rates, elimination rates, and biological half-lives. First-order, single-compartment models described the toxicokinetics for both species. Uptake of RDX into oligochaetes was relatively rapid (uptake clearance constant [k(u)] of 5.17 ml/g/h) compared to that in catfish (k(u) = 1.28 ml/g/h). However, elimination also was more rapid in oligochaetes, with biological half-lives of 0.28 and 1.09 h for oligochaetes and catfish, respectively. Thus, both species had very similar estimated BCFs of 2.1 ml/g for oligochaetes and 2.0 ml/g for catfish. Accumulation of RDX in fish that were fed oligochaetes exposed to an exceedingly high water concentration of RDX was minimal. The present investigation indicates that RDX uptake via the aqueous route is the expected dominant uptake pathway, with dietary uptake contributing minimally to the overall body burden in fish inhabiting RDX-contaminated sites. Because of the exceedingly low bioaccumulative potential and low reported toxicity of RDX, the presence of this explosive in aquatic systems is unlikely to pose unacceptable risks to invertebrates and fish.

Animals↗
PubMed2005

Reductive transformation of hexahydro-1,3,5-trinitro-1,3,5-triazine, octahydro-1,3,5,7-tetranitro-1,3,5,7-tetrazocine, and methylenedinitramine with elemental iron.

Reductive (pre)treatment with elemental iron is a potentially useful method for degrading nitramine explosives in water and soil. In the present study, we examined the kinetics, products, and mechanisms of hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX) and octahydro-1,3,5,7-tetranitro-1,3,5,7-tetrazocine (HMX) degradation with elemental iron. Both RDX and HMX were transformed with iron to formaldehyde, NH4+, N2O, and soluble products. The yields of formaldehyde were relatively constant (71% +/- 5%), whereas the yields of NH4+ and N2O varied, depending on the nitramine and the mechanism. The reactions most likely were controlled by a surface process rather than by external mass transfer. Methylenedinitramine (MDNA) was an intermediate of both RDX and HMX and was transformed quantitatively to formaldehyde with iron. However, product distributions and kinetic modeling results suggest that MDNA represented a minor reaction path and accounted for only 30% of the RDX reacted and 14% of the formaldehyde produced. Additional experiments showed that RDX reduction with elemental iron could be mediated by graphite and Fe2+ sorbed to magnetite, as demonstrated previously for nitroaromatics and nitrate esters. Methylenedinitramine was degraded primarily through reduction in the presence of elemental iron, because its hydrolysis was slow compared to its reactions with elemental iron and surface-bound Fe2+. Our results show that in a cast iron-water system, RDX may be transformed via multiple mechanisms involving different reaction paths and reaction sites.

Adsorption↗