This study presents evidence for the in vivo biotransformation of TCDD in the rat. Three male rats were implanted with indwelling bile loop cannulas. They were then given oral doses of 15 ug (14)C-TCDD/kg. After 2, 4, or 6 doses, the bile loop of one rat was opened and bile was collected for 24 hr. Biliary (14)C was excreted at a rate similar to the excretion of (14)C in the feces of rats fed (14)C-TCDD in a previous study. Selective solvent extraction revealed that the biliary (14)C activity was due to compound more polar than TCDD itself. Incubation of bile with beta-glucuronidase resulted in the extraction of more (14)C activity, implying the presence of glucuronide conjugates of (14)C-TCDD metabolites. Liquid chromatography of bile has revealed the presence of at least 5 distinct radioactive peaks, none of which was due to (14)C-TCDD. The data did not indicate extensive enterohepatic circulation of radioactivity derived from (14)C-TCDD. These results, in conjunction with the results of previous studies, indicate that TCDD is slowly metabolized in the liver to a variety of polar metabolites, which are then excreted in the bile.
Thin layer and gas chromatographic examination of the bile of dogs which were given tritium labelled TCDD revealed the presence of several polar biotransformation products. The structure of 5 phenolic metabolites was elucidated by combined gas chromatography-mass spectrometry. A metabolic breakdown scheme for TCDD in the dog is proposed /which includes 1,3,7,8-tetrachloro-2-methoxydibenzo-p-dioxin, 2,7,8-trichloro-3-methoxydibenzo-p-dioxin, trichloro-dimethoxydibenzo-p-dioxins, tetrachloro-dimethoxy diphenylether, and 1,2-dichloro-4,5-dimethyoxybenzene/.
The in vitro metabolism of 2,3,7,8-tetrachlorodibenzo-p-dioxin in isolated rat hepatocytes /was investigated/. ... The metabolites were ... identified as 1-hydroxy-2,3,7,8-TCDD and 8-hydroxy-2,3,7-trichlorodibenzo-p-dioxin.
来源:Hazardous Substances Data Bank (HSDB)
代谢
2,3,7,8-TCDD在狗体内的主要代谢物是1,3,7,8-四氯-2-羟基二苯并-p-二恶英。
The major metabolite /of 2,3,7,8-TCDD in dogs/ is 1,3,7,8-tetrachloro-2-hydroxydibenzo-p-dioxin.
CDDs are absorbed through oral, inhalation, and dermal routes of exposure. CDDs are carried in the plasma by serum lipids and lipoproteins, and mainly distributed in the liver and adipose tissue. CDDs are slowly metabolized to polar metabolites by the microsomal monooxygenase system. These metabolites can undergo conjugation with glucuronic acid and glutathione. They may increase the rate of their own metabolism by inducing both phase I and phase II enzymes. The major routes of excretion of CDDs are the bile and the faeces, though smaller amounts are excreted in the urine and via lactation. (L177)
IDENTIFICATION AND USE: 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a colorless to white crystalline solid. It has no known commercial applications, but it is used as a research chemical. It was tested, but never used commercially, as a flame proofing agent and as a pesticide against insects and wood-destroying fungi. TCDD occurred as a contaminant in chlorophenoxy herbicides, including 2,4,5-trichlorophenoxyacetic acid (2,4,5-T), that were widely used in the 1960s and 1970s to control weeds (including controlling weeds on pastureland and food crops) and as a defoliant during the Vietnam War. HUMAN EXPOSURE AND TOXICITY: The most commonly reported symptom related to TCDD exposure in man has been chloracne. The acneform lesions of the skin may develop a few weeks after the exposure and may persist for over a year following the cessation of exposure. Other skin problems include hyperpigmentation, hirsutism, increased skin fragility, and vesicular eruptions on exposed areas of the skin. Cancer incidence and cause specific mortality were examined in a group of 243 industrial workers who were exposed to TCDD. Increased cancer risk ratios were found with higher doses of TCDD and longer interval since first exposure, digestive and respiratory cancers in particular. Within the high dose group, total cancer mortality was increased 20 yr after first exposure as was respiratory cancer. This study provided further evidence of a relation between cumulative dose of TCDD and occurrence of both overall and digestive cancer. No evidence of an effect of TCDD on overall mortality or deaths due to circulatory disease was found and no cases of non-Hodgkin's lymphoma or soft tissue sarcoma have been found to date. ANIMAL STUDIES: The potency of TCDD to produce chloracne in the rabbit ear was tested. Threshold levels for the induction of lesions were between 1 ug for the pure compound and 160 ug when the compound was adsorbed onto charcoal. Chemical thyroidectomy effectively protected athyroid rats from mortality during 45 days after dosing with 100 ug TCDD/kg, whereas 70-80% of nonthyroidectomized-euthyroid and thyroidectomized-T4 (thyroxine)-maintained-euthyroid rats died within same period of time. These data indicate that thyroid hormones play an important role in mediating toxicity of TCDD. In order to test the potential of TCDD as a promoter of hepatocarcinogenesis, rats which had received a single 10 mg/kg dose of diethylnitrosamine following partial hepatectomy were given TCDD (0.14 and 1.4 ug/kg sc once every 2 weeks) for 7 months. Animals which received (a) only a single initiating dose of diethylnitrosamine after partial hepatectomy and no further treatment or (b) TCDD alone with no initiating dose of diethylnitrosamine exhibited relatively few enzyme altered foci and no hepatocellular carcinomas. However, animals initiated with diethylnitrosamine and then given TCDD had a marked increase in enzyme altered foci. At the higher dose of TCDD, hepatocellular carcinomas were present in five of seven rats. The total volume of the liver occupied by the enzyme altered foci, but not their number, increased with the dose of TCDD administered following diethylnitrosamine plus partial hepatectomy. TCDD was not mutagenic in any of several in vitro and in vivo short-term tests. No induction of gene mutations was seen in S. typhimurium strains TA98, TA100, TA1535, or TA1537 exposed to TCDD with or without S9 activation enzymes. No induction of trifluorothymidine resistance (gene mutations) was observed in L5178Y tk+/-mouse lymphoma cells tested with or without S9 activation. ECOTOXICITY STUDIES: TCDD is toxic to aquatic life. Medaka (Oryzias latipes) immersed in TCDD-treated water for 28 day, followed by immersion in clean water for up to 8 months, led to an increase in tumors at multiple sites, including gills, thyroid, and swimbladder. Guppies that survived exposure to TCDD for 10 days, showed necrosis of maxillary cartilage and fins.
CDDs bind to the aryl hydrocarbon (Ah) receptor and subsequently alter the transcription of several genes (oncogenes, growth factors, receptors, hormones, and drug-metabolizing enzymes). The affinity for the Ah receptor depends on the structure of the specific CDD. The change in gene expression may result from the direct interaction of the Ah receptor and its heterodimer-forming partner, the aryl hydrocarbon receptor nuclear translocator, with gene regulatory elements or the initiation of a phosphorylation/dephosphorylation cascade that subsequently activates other transcription factors. The change in transcription/translation of these genes is believed to be the cause of most of the toxic effects of CDDs. 2,3,7,8-tetrachlorodibenzo-p-dioxin's carcinogenicity is thought to be the result of its ability to alter the capacity of both exogenous and endogenous substances to damage the DNA by inducing CYP1A1- and CYP1A2-dependent drug-metabolizing enzymes. (L177)
Evaluation: There is limited evidence in humans for the carcinogenicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin. There is sufficient evidence in experimental animals for the carcinogenicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin. Overall Evaluation: 2,3,7,8-tetrachlorodibenzo-p-dioxin is carcinogenic to humans (Group 1). In making the overall evaluation, the Working Group took into consideration the following supporting evidence: (1) 2,3,7,8-TCDD is a multi-site carcinogen in experimental animals that has been shown by several lines of evidence to act through a mechanism involving the Ah receptor; (2) this receptor is highly conserved in an evolutionary sense and functions the same way in humans as in experimental animals; (3) tissue concentrations are similar in both heavily exposed human populations in which an increased overall cancer risk was observed and in rats exposed to carcinogenic dosage regimens in bioassays.
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is known to be a human carcinogen based on sufficient evidence of carcinogenicity from studies on humans, both epidemiological and on the mechanism of carcinogenesis.
Following single oral administration of 50 ug/kg bw (14)C-TCDD to rats, almost 30% was eliminated in feces during first 48 hr; excretion of (14)C activity via feces after this time was from 1-2%/day. After its absorption in the body, most of the activity derived from (14)C-TCDD is localized in liver and fat: the level in these tissues is 10 times that in other tissues. A total of 53.2% of the dose was eliminated via feces and 13.2% and 3.2% via urine and expired air respectively within 21 days.
In female guinea pigs administered a single oral dose of 2,3,7,8-TCDD only 1/2 of dose was absorbed. 22 days after dosing, fat, liver, adrenals and thymus contained 0.75, ...0.40, ...0.33, ...and 0.72% ...respectively.
... Distribution of (14)C-TCDD in the young following a single oral dose to the mother at the rate of 0.005 mg/kg was consistent with enzyme induction following a single oral dose. TCDD was found in fetuses sampled on gestation days 14, 18, or 21 but at far lower concentrations than in young examined 3, 7, 10, or 14 days after birth. Cross fostering tests indicated that TCDD was excreted in milk, and this accounted for the greater transfer to the neonate.
来源:Hazardous Substances Data Bank (HSDB)
吸收、分配和排泄
肝脏中TCDD的浓度被测量作为追踪这种化学物质通过肠道和皮肤途径被吸收的手段。发现（放射性标记的）化合物在肝脏中的积累提供了一个良好且可重复的方法，用于比较从不同配方中摄取TCDD的情况。在口服给予14.7 ng TCDD，使用50%乙醇作为溶剂后，24小时内肝脏中发现了总剂量的36.7%。当该化合物与土壤颗粒混合给药时，发生吸附，肝脏中发现的量只有大约一半。随着土壤和二噁英接触时间的增加，肝脏水平也会下降。活性炭上的吸附几乎完全阻止了该化合物的摄取。在TCDD以各种配方进行皮肤应用后，也观察到了类似的效果。在纯化合物与皮肤表面接触后，肝脏含量最高，为剂量的14.8%。土壤和活性炭的抑制效果甚至更为显著。将二噁英掺入凡士林（一种亲脂性软膏）后，肝脏中发现了剂量的1.4%，而当掺入含有15%水的聚乙二醇1500（一种亲水性软膏）后，肝脏中发现了14.1%。
The liver concentration of TCDD was measured as a means of following the uptake of this chemical by the intestinal and dermal routes. Accumulation of the (radiolabelled) compound in the liver was found to provide a good and reproducible method of comparing TCDD uptake from different formulations. After oral administration of 14.7 ng TCDD using 50% ethanol as vehicle, 36.7% of the total dose was found in the liver after 24 hr. When the cmpd was administered in a mixture with soil particles, adsorption occurred and only about half of this amount was found in the liver. The liver level also decreased with increasing duration of contact between the soil and the dioxin. Adsorption onto activated carbon almost completely prevented uptake of the cmpd. Similar effects were observed after dermal application of TCDD in the various formulations. The highest liver content, 14.8% of the dose, was found after contact of the pure cmpd with the skin surface. The inhibiting effects of soil and activated carbon were even more pronounced. After incorporation of the dioxin into vaseline (a lipophilic ointment), 1.4% of the dose was found in the liver, wheras, after incorporation into polyethylene glycol 1500 (a hydrophilic ointment) containing 15% water, 14.1% was found in the liver.
[EN] DISUBSTITUTED OCTAHY-DROPYRROLO [3,4-C] PYRROLES AS OREXIN RECEPTOR MODULATORS<br/>[FR] OCTAHYDROPYRROLO [3,4-C] PYRROLES DISUBSTITUÉS UTILISÉS COMME MODULATEURS DU RÉCEPTEUR DE L'OREXINE
申请人：JANSSEN PHARMACEUTICA NV
公开号：WO2012145581A1
公开（公告）日：2012-10-26
Disubstituted octahydropyrrolo[3,4-c]pyrrole compounds are described, which are useful as orexin receptor modulators. Such compounds may be useful in pharmaceutical compositions and methods for the treatment of diseased states, disorders, and conditions mediated by orexin activity, such as insomnia.
[EN] COMPOUNDS THAT MODULATE EGFR ACTIVITY AND METHODS FOR TREATING OR PREVENTING CONDITIONS THEREWITH<br/>[FR] COMPOSÉS MODULANT L'ACTIVITÉ DES RÉCEPTEURS EGFR ET MÉTHODES POUR TRAITER OU PRÉVENIR DES TROUBLES À L'AIDE DE CEUX-CI
申请人：GATEKEEPER PHARMACEUTICALS INC
公开号：WO2011140338A1
公开（公告）日：2011-11-10
Provided are compounds and methods for treating or preventing kinase-mediated disorders therewith.
提供了用于治疗或预防激酶介导的疾病的化合物和方法。
[EN] 5-O-SUBSTITUTED 3-N-PHENYL-1,3,4-OXADIAZOLONES FOR MEDICAL USE<br/>[FR] 3-N-PHÉNYL-1,3,4-OXADIAZOLONES 5-O-SUBSTITUÉES POUR UNE UTILISATION MÉDICALE
申请人：BIAL PORTELA & COMPANHIA S A
公开号：WO2009084970A1
公开（公告）日：2009-07-09
The present invention relates to compounds having a 5-O-substituted 3-N-phenyl-1,3,4-oxadiazolone structural unit which have unexpectedly high level of inhibition of FAAH (fatty acid amide hydrolase). (I)
[EN] 2-(1H-INDOLE-3-CARBONYL)-THIAZOLE-4-CARBOXAMIDE DERIVATIVES AND RELATED COMPOUNDS AS ARYL HYDROCARBON RECEPTOR (AHR) AGONISTS FOR THE TREATMENT OF E.G. ANGIOGENESIS IMPLICATED OR INFLAMMATORY DISORDERS<br/>[FR] DÉRIVÉS DE 2-(1H-INDOLE-3-CARBONYL)-THIAZOLE-4-CARBOXAMIDE ET COMPOSÉS CORRESPONDANTS UTILISÉS EN TANQUE QUE AGONISTES DU RÉCEPTEUR D'HYDROCARBURE ARYLE (AHR) UTILISÉS POUR LE TRAITEMENT DE, P.EX., DE L'ANGIOGENÈSE IMPLIQUÉE OU DE TROUBLES INFLAMMATOIRES
申请人：IKENA ONCOLOGY INC
公开号：WO2021127302A1
公开（公告）日：2021-06-24
2-(1H-lndole-3-carbonyl)-thiazole-4-carboxamide derivatives and the corresponding imidazole, oxazole and thiophene derivatives and related compounds as aryl hydrocarbon receptor (AHR) agonists for the treatment of angiogenesis implicated disorders, such as e.g. retinopathy, psoriasis, rheumatoid arthritis, obesity and cancer, or inflammatory disorders. The present description discloses the synthesis and characterisation of exemplary compounds as well as pharmacological data thereof (e.g. pages 27 to 32 and 59 to 219; examples 1 to 8; compounds 1-1 to 1-97; tables 1-a, 2 and 3).
[EN] NOVEL COMPUNDS, PHARMACEUTICAL COMPOSITIONS CONTAINING SAME, AND METHODS OF USE FOR SAME<br/>[FR] NOUVEAUX COMPOSÉS, COMPOSITIONS PHARMACEUTIQUES LES CONTENANT ET MÉTHODES D'UTILISATION DESDITS COMPOSÉS
申请人：FASGEN INC
公开号：WO2004005277A1
公开（公告）日：2004-01-15
A pharmaceutical composition comprising a phamaceurtical diluent and a compound of formula IV wherein R21= H, C1-C20 alkyl, cycloalkyl, alkenyl, aryl, arylalkyl, or alkylaryl, -CH2OR25, -C(O)R25, -CO(O)R25, -C(O)NR25R26, -CH2C(O)R25, or -CH2C(O)NHR25, where R25 and R26 are each independently H, C1-C10 alkyl, cycloalkyl, alkenyl, aryl, arylalkyl, or alkylaryl, optionally containing one or more halogen atoms. R22 = -OH, -OR27, -OCH2C(O)R27, -OCH2C(O)NHR27, -OC(O)R27, -OC(O)OR27, -OC(O)NHNH-R5, or -OC(O)NR27R28, where R27 and R28 are each independentlyH, C1 -C20 alkyl, cycloalkyl, alkenyl, aryl, arylalkyl, or alkylaryl, and where R27 and R28 can each optionally contain halogen atoms; R23 and R24, the same or different from each other, are C1-C20 alkyl, cycloalkyl, alkenyl, aryl, arylalkyl, or alkylaryl. Methods of using such formulations for the treatment of cancer, to effect weight loss, to treat microbially-based infections, to inhibit neuropeptide-Y and/or fatty acid synthase, and to stimulate CPT-1.
