Disease relevance of DET

• Toxicity of diethyltoluamide-containing insect repellents [1].
• RESULTS: The DET was positive for myocardial ischemia in 2,854 (35%) patients and negative in 4,479 (61%) patients [2].
• Thirty six DET patients had dysplasia on at least one examination: two patients with high grade dysplasia (HGD) were colonoscoped on suspicion of carcinoma, one asymptomatic patient had HGD at first colonoscopy and one patient had HGD on his sixth colonoscopy, all having carcinomas resected at surgery; the remainder had low grade dysplasia (LGD) [3].
• A slow releasing NO donor DETA NONOate (DETA/NO NOC-18) dose dependently inhibited lucigenin-enhanced chemiluminescence from phorbol ester-stimulated polyp fragments, with an EC50 of 1.5 mM [4].
• Similarly, hypoxia (2% oxygen) or low levels of an NO donor (100 microM DETA/NO) caused little or no neuronal death in nonactivated cultures [5].

Psychiatry related information on DET

• Current repellents, usually based on DEET, inhibit host finding by impeding insect olfaction, but have significant drawbacks [6].
• Infusion of a NO donor, (Z)-1-[N-(2-aminoethyl)-N-(2-ammonioethyl)amino]diazen-1-ium-1,2diolate (DETA/NO), produced an increase in NREM that closely resembled NREM recovery after prolonged wakefulness [7].
• 2. DEET (1a) produces three major metabolites, N-ethyl-m-toluamide (1b), N,N-diethyl-m-(hydroxymethyl)benzamide (2a) and N-ethyl-m-(hydroxymethyl)benzamide (2b), and, at low substrate concentrations or extended reaction times, two minor metabolites, toluamide (1c) and N,N-diethyl-m-formylbenzamide (3a) [8].
• The typical poisoning symptom of butylidenephthalide was lethargy of treated mites, leading to death without knockdown, whereas benzyl benzoate and DEET caused death following uncoordinated behavior [9].
• N,N-diethyl-3-methylbenzamide is effective against a variety of mosquitoes, flies, fleas, and ticks, and its protection efficacy depends on factors such as type of formulation, application pattern, physical activity of the user, environment, and species and feeding behavior of the insects [10].

High impact information on DET

• Our data indicates that COP10 defines a possible E2 activity, thus validating the working hypothesis that the pleiotropic COP/DET/FUS group of proteins defined a protein ubiquitination pathway [11].
• No effect on expression of cell adhesion molecules was observed with DETA alone [12].
• These signaling components include the red/far-red light receptors, phytochromes, at least one blue light receptor, and negative regulatory genes (DET, COP, and FUS) that act downstream from the photoreceptors in the nucleus [13].
• Analysis of the mutational effects of the COP/DET/FUS loci on genome expression profiles reveals their overlapping yet not identical roles in regulating Arabidopsis seedling development [14].
• Microarray gene expression profiling was used to examine the role of pleiotropic COP/DET/FUS loci as well as other partially photomorphogenic loci during Arabidopsis seedling development and genome expression regulation [14].

Chemical compound and disease context of DET

• RESULTS: Overexpression of antioxidant enzymes provided significant protection against the toxicity of SNAP, SNP and SIN-1, with an individual specificity related to their chemical characteristics, but was without effect upon the toxicity of DETA/NO [15].
• Indicators of energy metabolism, adenosine, lactate and pyruvate increased during prolonged wakefulness and DETA/NO infusion, whereas L-NAME infusion during SD prevented the increases [7].
• Necrotic death, induced by hypoxia plus DETA/NO, was increased further by deoxyglucose, an inhibitor of glycolysis, suggesting that necrosis was mediated by energy depletion [5].
• They also uncovered strong associations (relative risks 4-8) suggesting that these symptom complexes were related to wartime exposure to combinations of organophosphate pesticides, chemical nerve agents, high concentration DEET insect repellant, and symptoms of advanced acute toxicity after taking pyridostigmine [16].
• This study clearly demonstrates that alternative formulations can be developed for DEET aimed at reduced permeation and toxicity unlike the current formulations some of which contain ethanol which has been shown to enhance permeation of DEET [17].

Biological context of DET

• We report that administration of a nitric oxide donor, (Z)-1-[N-(2-aminoethyl)-N-(2-ammonioethyl) aminio]diazen-1-ium-1,2-diolate (DETA/NONOate), to young adult rats significantly increases cell proliferation and migration in the subventricular zone and the dentate gyrus [18].
• Rapid progress in eukaryotic gene repression mechanisms in general, and light control of plant gene expression in particular, sheds new light on how a class of ten pleiotropic COP/DET/FUS genes might function to down-regulate light-inducible genes in plants [19].
• Chromosome damage and repair in quiescent normal human fibroblasts (PA2 and DET 550) were assayed by the premature chromosome condensation technique in which the G1 prematurely condensed chromosomes are condensed and easily enumerated [20].
• Combined exposure to DEET (N,N-diethyl-m-toluamide) and permethrin: pharmacokinetics and toxicological effects [21].
• Nitric oxide (NO) released from (Z)-1-[N-(2-aminoethyl)-N-(2-ammonioethyl)amino]diazen-1- ium-1,2-diolate (DETA/NO or NOC-18) induces apoptosis in human leukemia HL-60 cells [22].

Anatomical context of DET

• Treatment with DETA/ NONOate also increases neurogenesis in the dentate gyrus [18].
• Furthermore, administration of DETA/NONOate to rats subjected to embolic middle cerebral artery occlusion significantly increases cell proliferation and migration in the subventricular zone and the dentate gyrus, and these rats exhibit significant improvements of neurological outcome during recovery from ischemic stroke [18].
• Supplementation of ICAM-1 mutant cells with the NO donor DETA NONOate (0.1 microM) corrected the migration defect, diminished stress fiber formation, and enhanced pseudopod and uropod formation [23].
• The inhibition of endothelial cell tube formation by VPA was prevented by addition of the nitric oxide donor (Z)-1-[2-(2-aminoethyl)-N-(2-ammonioethyl)amino]diazen-1-ium-1,2-diolate (DETA NONOate) [24].
• In this study, we isolated a HL-60 variant cell line, HL-NR6, that is resistant to DETA/NO toxicity as assessed by DNA fragmentation, morphology, and colony forming ability [22].

Associations of DET with other chemical compounds

• NO donors (SNAP and DETA NONOate) inhibited elastase in a dose-dependent manner as did a cGMP mimetic (8-pCPT-cGMP) [25].
• Cell death in response to OGD, alone or in combination with hydrogen peroxide, lipopolysaccharides, interleukin-1beta, tissue necrosis factor-alpha, or nitric oxide (NO) donor diethylenetriamine/nitric oxide adduct (DETA/NO) was quantified as the ratio of propidium iodide to calcein AM-positive cells [26].
• Similarly, addition of the NO donor DETA NONOate and 8-bromo-cGMP to the culture medium significantly decreased MMP-2 and MMP-9 activities in the conditioned medium collected 24 hours after treatment [27].
• RESULTS: The production of nitrite/nitrate and VEGF-D in K1 cells was increased by treatment with the NO donor, (Z)-1-[N-(2-aminoethyl)-N-(2-ammonioethyl)amino]diazen-1-ium-1,2-diolate (DETA NONOate) [28].
• Moreover, the SOD mimetic Mn(III) tetrakis(1-methyl-4-pyridyl) porphyrin and exogenous catalase effectively attenuated DETA/NO-elicited DNA fragmentation in HL-60 cells [22].

Gene context of DET

• COP1, another COP/DET/FUS protein, is itself not a subunit of the COP9 signalosome [29].
• Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) inhibition, carbonylation and translocation from cytoplasm to nucleus and DNA fragmentation were also induced by DETA/NO exposure [30].
• Among 15 cDNA-expressed P450 enzymes examined, CYP1A2, 2B6, 2D6*1 (Val(374)), and 2E1 metabolized DEET to the BALC metabolite, whereas CYP3A4, 3A5, 2A6, and 2C19 produced the ET metabolite [31].
• Under these conditions, IL-4 secretion was not inhibited and IL-5 secretion was inhibited to a lesser extent (P < 0.01 for SNAP and DPTA, P > 0.05 for DETA) [32].
• CYP2B6 is the principal cytochrome P450 involved in the metabolism of DEET to its major BALC metabolite, whereas CYP2C19 had the greatest activity for the formation of the ET metabolite [31].

Analytical, diagnostic and therapeutic context of DET

• Of the DET patients, 100 constituted an ongoing surveillance group (354 colonoscopies) in which LGD was common, being seen on at least one occasion in 33% of patients (16.4% of examinations), but HGD was noted only once with a Dukes A cancer found at surgery [3].
• Northern and Western blot analysis demonstrated increased flavohemoglobin expression after DETA/NO exposure and the strongest expression in HB101 carrying hmp on a multicopy plasmid [33].
• Protein levels of soluble fibronectin, assessed in conditioned medium by ELISA, were decreased by 14 +/- 4% and 21 +/- 4% after 48 h treatment with 1 microM bradykinin and 100 microM DETA NONOate, respectively [34].
• HPLC analysis of urine from rats in the ADME phase of the study showed that DEET was metabolized completely in all treatment groups, with little or no parent compound excreted in the urine [35].
• In the remaining 521 cycles, eSET was performed in 111 cycles (19%), while in 410 cycles, no good quality embryo was available resulting in the transfer of two embryos (double embryo transfer, DET) [36].

References