Among the pentaCDFs, the rate of transformation of 1,2,3,4,8-, 1,2,3,7,8-, and 2,3,4,7,8-pentaCDF was high, moderate, and low, respectively. The predominant metabolite (out of 7 compounds found) of 1,2,3,7,8-pentaCDF was a hydroxy-pentaCDF. According to investigators, formation of 6,7-dihydroxy-pentaCDF may also have occurred. Tetrachlorinated compounds were also identified. The major metabolite (out of 12 compounds found) of 1,2,3,7,8-pentaCDF was a dihydroxy-pentaCDF; other derivatives included monohydroxy-tetra- and pentaCDFs and a trichloro-dihydroxyCDF. Metabolism of 2,3,4,7,8-pentaCDF led to 2 major compounds (out of 10 compounds found), a methoxy-pentaCDF, and a dimethoxy-pentachlorobiphenyl, the latter formed by ether cleavage. A sulfur containing metabolite was also present. Unmetabolized pentaCDFs were also excreted in the bile. Only a small amount of a hydroxy-pentaCDF was identified from 1,2,3,6,7,8- hexaCDF, whereas no metabolites were detected from 1,2,3,4,6,7-heptaCDF. /Pentachlorodibenzofurans/
Limited data suggest that autoinduction of metabolism and biliary excretion does occur for PCDFs, in contrast to PCDDs. Pretreatment of rats with 2,3,7,8-TCDF (1.0 umol/kg, 3 days earlier) significantly increased the biliary excretion of a subsequent dose of (14C)2,3,7,8-TCDF. The naive rats excreted 5.7 + or - 2.4% of the dose over the initial 8 hr, while the pretreated rats excreted 13.2 + or - 3.2% of the (14C)2,3,7,8-TCDF. Similarly, pretreatment of rats with 2,3,4,7,8-pentaCDF (500 ug/kg, /orally/, 3 days earlier) resulted in a two-fold increase in the biliary elimination of a subsequent dose of (14C)2,3,4,7,8-pentaCDF. These results suggest that pretreatment with 2,3,7,8-TCDF and 2,3,4,7,8-pentaCDF induces the metabolism of these congeners.
No information on the metabolism of dibenzofuran in mammalian organisms was found in the available literature. The bacteria Sphingomonas, Brevibacterium, Terrabacter, and Staphylococcus auricularis degrade dibenzofuran to 2,2',3-trihydroxybiphenyl via dibenzofuran 4,4a-dioxygenase. (L952)
Halogenated dibenzofurans (PCDFs and PBDFs) bind the aryl hydrocarbon receptor (AhR), which increases its ability to activate transcription in the XRE (xenobiotic resoponse element) promoter region. Specifically AhR binds to the PCDF, translocates it to the nucleus and together with hydrocarbon nuclear translocator (ARNT) and xenobiotic responsive element (XRE) increases the expression of CYP1A1 and aryl hydrocarbon hydroxylase (CYP1B1). AhR signaling also increseases conversion of arachidonic acid to prostanoids via cyclooxygenase-2, alters Wnt/beta-catenin signaling downregulating Sox9 and alters signaling by receptors for inflammatory cytokines. AhR signalling also alters proteasomal degradation of steroid hormone receptors, alters cellular UVB stress response and changes the differentiation of certain T-cell subsets. The resulting AhR mediated activation and alteration leads to body weight loss, cancer and thymic atrophy (characteristic of immune and endocrine disruption) which are common toxic responses to PCDFs and related toxic halogenated aryl hydrocarbons.
Evaluation: There is inadequate evidence in humans for the carcinogenicity of polychlorinated dibenzofurans. There is limited evidence in experimental animals for the carcinogenicity of 2,3,4,7,8-pentachlorodibenzofuran. Overall evaluation: Polychlorinated dibenzofurans are not classifiable as to their carcinogenicity to humans (Group 3). /Polychlorinated dibenzofurans/
Male Fischer-344 rats received a single oral dose of 14C-2,3,4,7,8-pentaCDF at 34-338 ug/kg, and 3 days after dosing, CDF-derived radioactivity was most concentrated in the liver (>50%), followed by adipose (6%), skin (0.9%), and muscle (0.5%). When expressed as percentage of the dose per gram of tissue, the liver had 5.9% followed by adipose with 0.3%, and adrenal with 0.15%. Regardless of how the results were expressed, tissue distribution was not dose-related, and all other tissues and organs had only traces of radioactivity. .../About/ 30% of the CDF-derived radioactivity was excreted in the feces over a 3 day period, regardless of the dose. No radioactivity was detected in expired air, and urinary excretion accounted for <0.01% of the dose per day. Analysis of fecal samples 1 day after dosing suggested that >50% of the CDF-derived radioactivity was parent compound; however, 2 days later this fell to 20%. These results, when compared with those obtained with the tetra-substituted congener in rats, suggest that by adding a chlorine substitute to position four in the CDF ring, excretion rate is decreased by half. .../This/ is related to the metabolic handling of the two congeners. /2,3,4,7,8-Pentachlorodibenzofuran/
Young male Wistar rats absorbed approximately 6.8% of a single oral dose of 1.0 mg 2,3,4,7,8-pentaCDF/kg bw given in salad oil. The daily fecal excretion was about 0.1% of the administered dose/day, whereas no 2,3,4,7,8-pentaCDF was detected in urine. Four weeks after dosing the retention of 2,3,4,7,8-pentaCDF in the liver was 48.8% of the dose. The addition of 5% of activated charcoal beads to the diet, one week after dosing and throughout the study, increased the fecal elimination of 2,3,4,7,8-pentaCDF about 3-fold, but had no effect on urinary elimination. Both the liver and extrahepatic tissues, except the kidney, from rats on basal diet supplemented with activated charcoal beads had lower levels of 2,3,4,7,8-pentaCDF than rats on basal diet only. /2,3,4,7,8-Pentachlorodibenzofuran/
The oral bioavailability of 2,3,4,7,8-pentaCDF (2,3,4,7,8-pentachlorodibenzofuran) in corn oil is similar to that of TCDD. Furthermore, 2,3,4,7,8-pentaCDF absorption was independent of the dose (0.1, 0.5, or 1.0 umol/kg).
Studies in the rat, guinea pig, hamster, and mouse have found that essentially all of the TCDD-derived radioactivity excreted in the urine and bile corresponds to metabolites of TCDD. The apparent absence of TCDD metabolites in liver and fat suggests that once formed, the metabolites of TCDD are excreted readily. Thus, urinary and biliary elimination of TCDD depends on metabolism of the toxin. The more limited data for other compounds also suggest that this relationship may be true for ...1,2,3,7,8-pentaCDF, /and/ 2,3,4,7,8-pentaCDF... .
Estimation of dioxin emission from fires in chemicals
摘要：
The formation of the 17 toxic 2,3,7,8-substituted PCDDs and PCDFs during combustion of selected chemicals were measured by high-resolution GC/MS. The 16 chemicals studied were commonly used chlorinated pesticides, industrial chemicals, and PVC. In a series of experiments carried out in a DIN 53,436 furnace, 2.5 g of these compounds were burned at 500 degrees C and 900 degrees C, respectively. The resultant yields ranged from 740 ng ITEQ/g for pentachlorophenol, to below 0.01 ng ITEQ/g for PVC and dichlobenil. The results show that some chemicals generate PCDD/F in very high possibly dangerous - amounts during burning, whereas others generate insignificant amounts. The influence of scale were studied for chlorobenzene and 4-chloro-3-nitro-benzoic acid in additional experiments, carried out in a cone calorimeter burning 20 g substance, and in ISO 9705 room test burning about 50 kg. A good agreement between the results for large and small scale indicated that formation of PCCD/F during a fire may be estimated from laboratory experiments. This suggest laboratory test may be used to screen for chemicals posing a hazard for release of PCDD/F during fires. (C) 1999 Elsevier Science Ltd. All rights reserved.
作者：Mariusz K. Cieplik、Jose Pastor Carbonell、Christina Muñoz、Sarah Baker、Sophie Krüger、Per Liljelind、Stellan Marklund、Robert Louw
DOI：10.1021/es026292g
日期：2003.8.1
sintering facility could satisfactorily imitate the large-scale process, in part or as a whole. Results obtained with realistic feed mixtures point at dioxin formation in the sinter bed at levels significant enough to explain a major part of the outputs observed in the real-life process. With approximately 8 ppm (wt) of chloride added as NaCl, the PCDD/F output doubled, but with the same proportion of
PCDD/DF formations by the heterogeneous thermal reactions of phenols and their TiO2 photocatalytic degradation by batch-recycle system
作者：Hajime Muto、Koki Saitoh、Hitoshi Funayama
DOI：10.1016/s0045-6535(00)00552-x
日期：2001.10
and dibenzofurans (PCDD/DFs) formation by the thermal reactions of phenols with CuCl2 under oxygen flux were carried out in relation to their formation mechanisms. To evaluate the effect of photocatalytic degradation of titaniumdioxide (TiO2) thin film prepared by the sol-gel method, the photocatalysis of PCDD/DFs in acetonitrile/water solution by batch-recycle system was conducted. For the thermal reaction
Emissions of polychlorinated dibenzo-p-dioxins and dibenzofurans from catalytic and thermal oxidizers burning dilute chlorinated vapors
作者：John R. Hart
DOI：10.1016/j.chemosphere.2003.10.017
日期：2004.3
(ng/dscm)=8.4 exp(-0.0084T degrees C); (2) dioxin/furan production occurs at the combustion catalyst; (3) small variations in temperature cause large changes in the congener distribution of the dioxin and furan isomers; (4) molar TEQ yields from the parent compounds fed to the oxidizers are very small (10(-9)-10(-13)); (5) catalytic and thermal oxidizers may destroy dioxins fed from the ambient air; and (6)
Emission Factors and Importance of PCDD/Fs, PCBs, PCNs, PAHs and PM<sub>10</sub> from the Domestic Burning of Coal and Wood in the U.K.
作者：Robert G. M. Lee、Peter Coleman、Joanne L. Jones、Kevin C. Jones、Rainer Lohmann
DOI：10.1021/es048745i
日期：2005.3.1
fuels. However, their combined emissions from the domestic burning of coal and wood would contribute only a few percent to annual U.K.emission estimates. Emissions of PAHs and PM10 were major contributors to U.K. national emission inventories. Major emissions were found from the domestic burning for Cl1,2,3DFs, while the contribution of PCDD/F-sigmaTEQ to total U.K.emissions was minor.
本文介绍了当煤和木材经过受控燃烧实验时针对一系列持久性有机污染物（POPs）得出的排放因子（EFs），旨在模拟空间供暖的家庭燃烧。排放了各种各样的持久性有机污染物，煤炭的排放量高于木材的排放量。对于颗粒物，PM10（大约10 g / kg燃料）和多环芳烃（对于sigmaPAHs大约100 mg / kg燃料）获得了最高的EF。对于氯化物，多氯联苯（PCB）的EF最高，而多氯萘（PCN），二苯并-对-二恶英（PCDD）和二苯并呋喃（PCDF）的丰度较低。对于sigmaPCB，EF大约为1000 ng / kg燃料，对于sigmaPCNs大约为100s ng / kg燃料，对于sigmaPCDD / Fs大约为100 ng / kg燃料。该研究证实，一氯化至三氯化二苯并呋喃Cl1,2,3DFs是低温燃烧过程（如煤炭和木材的国内燃烧）的有力指标。结论是，在固体燃料燃烧期间通常形成许多PCB和PC
[EN] PFKFB3 INHIBITORS AND THEIR USES<br/>[FR] INHIBITEURS DE PFKFB3 ET LEURS UTILISATIONS
申请人：GERO DISCOVERY LLC
公开号：WO2020080979A1
公开（公告）日：2020-04-23
This disclosure relates to new phthalimide and isoindolinone derivatives and other PFKFB3 inhibitors for use in the treatment of diseases. The invention further relates to pharmaceutical compositions containing such PFKFB3 inhibitors, methods of preparation thereof, methods for their use as therapeutic agents, and methods of preparation of a medicament for use in therapy, as well as kits and other inventiions comprising such PFKFB3 inhibitors. These PFKFB3 inhibitors are useful for the treatment and prophylaxis of cancer, neurodegenerative diseases, autoimmune diseases, inflammatory disorders, multiple sclerosis, metabolic diseases, inhibition of angiogenesis and other diseases and conditions, where the modulation of PFKFB3 and/or PFKFB4 has beneficial effect as well as neuroprotection.
