Category: 40180-04-9

Ahmed, Nahed K. published the artcileComparison and characterization of mammalian xenobiotic ketone reductases, Quality Control of 40180-04-9, the main research area is drug metabolism ketone reductase enzyme; liver kidney ketone drug reduction.

Rabbit liver extracts catalyzed the reduction of the ketone group of the following drugs: oxisuran [27302-90-5], metyrapone [54-36-4], naloxone [465-65-6], naltrexone [16590-41-3], 3,7-dimethyl-1-(5-oxohexyl)-xanthine (3,7-DMX) [6493-05-6], and daunorubicin [20830-81-3]. The reductases catalyzing these reactions were extracted from rabbit liver and characterized. Significant activity was also extracted from human liver, but rat and mouse livers had very low levels of the ketone reductases. Although reductase activity occurs mainly in the liver and kidney, detectable activity was also observed in spleen, lung, and brain. All drug reductases displayed an acid pH optimum, had an absolute requirement for NADPH as cofactor, and occurred primarily as cytoplasmic enzymes. Although the reductases elute from gel filtration chromatog. in slightly different volumes, all enzymes have mol. weights in the range of 32,000 to 38,000 daltons. The drug reductases were not significantly inhibited by phenobarbital or by pyrazole, suggesting that the ketone reductases exist as a class of enzymes distinct from aromatic aldehyde reductases and classical alc. dehydrogenase. The ketone reductases were inhibited by the plant flavonoid quercitrin. Isoelec. focusing resolved drug reductases into multiple forms. The major activities for 3,7-DMX, oxisuran, and metyrapone focused as a single sym. coincident peak with a pI of 4.8, whereas the majority of naloxone and naltrexone reductases focused as heterogeneous bands above pH 6.0. Minor forms of most of the drug reductases were also evident.

Journal of Pharmacology and Experimental Therapeutics published new progress about Brain. 40180-04-9 belongs to class benzothiophene, name is 2-(2,3-Dichloro-4-(thiophene-2-carbonyl)phenoxy)acetic acid, and the molecular formula is C13H8Cl2O4S, Quality Control of 40180-04-9.

Referemce:
Benzothiophene – Wikipedia,
Benzothiophene | C8H6S – PubChem

Acosta, Daniel published the artcileLack of cytotoxicity of ticrynafen in primary cultures of rat liver cells, HPLC of Formula: 40180-04-9, the main research area is tricrynafen cytotoxicity liver.

Primary cultures of hepatocytes obtained from neonatal Sprague-Dawley rats were grown in arginine-deficient, ornithine-supplemented medium to inhibit fibroblastic overgrowth and to selectively isolate relatively pure cultures of parenchymal hepatocytes. This system of primary hepatocytes was used to study the potential cytotoxicity of ticrynafen (I) [40180-04-9] by measuring cytoplasmic enzyme leakage, cell viability, and total protein per culture dish. Hepatic cultures were treated with the drug in concentrations ranging from 10-3 M to 10-6 M and for durations from 2 to 8 h. The results of the study indicate that ticrynafen was minimally toxic to the hepatocytes.

Toxicology Letters published new progress about Liver. 40180-04-9 belongs to class benzothiophene, name is 2-(2,3-Dichloro-4-(thiophene-2-carbonyl)phenoxy)acetic acid, and the molecular formula is C13H8Cl2O4S, HPLC of Formula: 40180-04-9.

Referemce:
Benzothiophene – Wikipedia,
Benzothiophene | C8H6S – PubChem

Hildebrandt, E. published the artcileIndirect inhibition of vitamin K epoxide reduction by salicylate, Application of 2-(2,3-Dichloro-4-(thiophene-2-carbonyl)phenoxy)acetic acid, the main research area is salicylate vitamin K epoxide reductase.

Salicylate  [69-72-7] antagonizes the vitamin K  [12001-79-5]-dependent biosynthesis of clotting factors in the rat and produces an elevation of the ratio of vitamin K epoxide  [25486-55-9] to vitamin K in the liver. Vitamin K epoxide is reduced to vitamin k by a vitamin K epoxide reductase  [55963-40-1], and 1 mM salicylate was required to cause a 50% inhibition of the dithiothreitol-dependent in-vitro reduction of vitamin K epoxide by this enzyme. This enzyme was, however, inhibited 50% by as little as 70-80 μM salicylate when reducing equivalent for the reaction were furnished by endogenous cytosolic reductants. This effect on the cytosolic reductant supply was shown to be unrelated to a previously demonstrated inhibition of DT-diaphorase by salicylate. The concentrations of salicylate at which significant inhibitory effects are exerted are in-vitro (50-100 μM) are below the 200 μM levels observed in the livers of rats given an anticoagulating dose of salicylate.

Journal of Pharmacy and Pharmacology published new progress about Liver. 40180-04-9 belongs to class benzothiophene, name is 2-(2,3-Dichloro-4-(thiophene-2-carbonyl)phenoxy)acetic acid, and the molecular formula is C13H8Cl2O4S, Application of 2-(2,3-Dichloro-4-(thiophene-2-carbonyl)phenoxy)acetic acid.

Referemce:
Benzothiophene – Wikipedia,
Benzothiophene | C8H6S – PubChem

Ayotte, P. published the artcileFailure of phenobarbital or butanediol pretreatment to potentiate tienilic acid hepatotoxicity in vivo in the rat, Product Details of C13H8Cl2O4S, the main research area is tienilate liver toxicity phenobarbital butanediol.

Tienilic acid  [40180-04-9], a uricosuric diuretic, has been associated with hepatocellular injury in humans as a low-incidence adverse reaction. This phenomenon suggests that a metabolic idiosyncrasy may be involved. The effect of phenobarbital  [50-06-6] and 1,3-butanediol  [107-88-0] pretreatment, prior to tienilic acid challenge (50 or 100 mg/kg, i.v.) on rat hepatic function was studied in vivo. The following parameters were assessed: plasma alanine aminotransferase activity, plasma bilirubin concentration, and bile flow. The results show that neither pretreatment would reveal that tienilic acid possesses hepatotoxic properties in the rat. The discrepancies between these results observed in vivo and those obtained by others in the isolated perfused rat liver suggest: a) that a metabolite formed (under normal conditions) via the phenobarbital- or butanediol-inducible forms of cytochrome P 450  [9035-51-2] is not a likely part of the hepatotoxic sequence of events; b) that the isolated perfused rat liver model in this case is not representative of the in vivo situation.

Archives Internationales de Pharmacodynamie et de Therapie published new progress about Liver. 40180-04-9 belongs to class benzothiophene, name is 2-(2,3-Dichloro-4-(thiophene-2-carbonyl)phenoxy)acetic acid, and the molecular formula is C13H8Cl2O4S, Product Details of C13H8Cl2O4S.

Referemce:
Benzothiophene – Wikipedia,
Benzothiophene | C8H6S – PubChem

Dansette, P. M. published the artcileOxidative activation of the thiophene ring by hepatic enzymes. Hydroxylation and formation of electrophilic metabolites during metabolism of tienilic acid and its isomer by rat liver microsomes, Application of 2-(2,3-Dichloro-4-(thiophene-2-carbonyl)phenoxy)acetic acid, the main research area is thiophene metabolism liver monooxygenase cytochrome; tienilic acid metabolism liver cytochrome P450.

Tienilic acid (TA) is metabolized by liver microsomes from phenobarbital-treated rats in the presence of NADPH with the major formation of 5-hydroxytienilic acid (5-OHTA) which is derived from the regioselective hydroxylation of the thiophene ring of TA. During this in vitro metabolism of TA, reactive electrophilic intermediates which bind irreversibly to microsomal proteins are formed. 5-Hydroxylation of TA and activation of TA to reactive metabolites which covalently bind to proteins required intact microsomes, NADPH and O and are inhibited by metyrapone and SKF 525A, indicating that they are dependent on monooxygenases using cytochromes P 450. Microsomal oxidation of an isomer of TA (TAI) bearing the aroyl substituent on position 3 (instead of 2) of the thiophene ring also leads to reactive intermediates able to bind covalently to microsomal proteins. Covalent binding of TAI, as that of TA, depends on cytochrome P 450-dependent monooxygenases and is almost completely inhibited in the presence of S-containing nucleophiles such as glutathione, cysteine or cyteamine. These results show that 5-OHTA, which has been reported as the major metabolite of TA in vivo in humans, is formed by liver microsomes by a cytochrome P 450-dependent reaction. They also show that 2 thiophene derivatives, TA and TAI, bind to microsomal proteins after in vitro metabolic activation, TAI giving a much higher level of covalent binding than TA (about 5-fold higher) and a much higher covalent binding:stable metabolites ratio (4 instead of 0.5).

Biochemical Pharmacology published new progress about Liver. 40180-04-9 belongs to class benzothiophene, name is 2-(2,3-Dichloro-4-(thiophene-2-carbonyl)phenoxy)acetic acid, and the molecular formula is C13H8Cl2O4S, Application of 2-(2,3-Dichloro-4-(thiophene-2-carbonyl)phenoxy)acetic acid.

Referemce:
Benzothiophene – Wikipedia,
Benzothiophene | C8H6S – PubChem

Dansette, P. M. published the artcileHydroxylation and formation of electrophilic metabolites of tienilic acid and its isomer by human liver microsomes: catalysis by a cytochrome P450 IIC different from that responsible for mephenytoin hydroxylation, Related Products of benzothiophene, the main research area is tienilate isomer metabolism liver microsome; cytochrome P450 tienilate isomer metabolism liver.

Tienilic acid (TA; I) is metabolized by human liver microsomes in the presence of NADPH with the major formation of 5-hydroxytienilic acid (5-OHTA) which is derived from the hydroxylation of the thiophene ring of TA. Besides this hydroxylation, TA is oxidized into reactive metabolites which covalently bind to microsomal proteins. Oxidation of an isomer of tienilic acid (TAI) by human liver microsomes, gives a much high level of covalent binding to proteins. Both covalent binding of TA and TAI metabolites are almost completely suppressed in the presence of glutathione. These three activities of human liver microsomes (TA 5-hydroxylation, covalent binding of TA and TAI metabolites) seem dependent on the same cytochrome P 450 of the IIC subfamily, since (i) antibodies against human liver cytochromes P 450 IIC strongly inhibit these three activities, (ii) there is a clear correlation between these activities in various human liver microsomes, and (iii) TA acts as a competitive inhibitor for TAI activation into electrophilic metabolites (Ki ≃ 25 μM) and TAI inhibits TA 5-hydroxylation. However cross inhibition experiments indicate that tienilic acid hydroxylation and mephenytoin hydroxylation, a typical reaction of some human liver P 450 IIC isoenzymes, are not catalyzed by the same member of the P 450 IIC subfamily.

Biochemical Pharmacology published new progress about Liver. 40180-04-9 belongs to class benzothiophene, name is 2-(2,3-Dichloro-4-(thiophene-2-carbonyl)phenoxy)acetic acid, and the molecular formula is C13H8Cl2O4S, Related Products of benzothiophene.

Referemce:
Benzothiophene – Wikipedia,
Benzothiophene | C8H6S – PubChem

Whitby, Landon R. published the artcileQuantitative Chemical Proteomic Profiling of the in Vivo Targets of Reactive Drug Metabolites, Synthetic Route of 40180-04-9, the main research area is troglitazone acetaminophen clozapine tienilate hepatotoxicity proteomic profiling drug metabolite.

Idiosyncratic liver toxicity represents an important problem in drug research and pharmacotherapy. Reactive drug metabolites that modify proteins are thought to be a principal factor in drug-induced liver injury. Here, the authors describe a quant. chem. proteomic method to identify the targets of reactive drug metabolites in vivo. Treating mice with clickable analogs of four representative hepatotoxic drugs, the authors demonstrate extensive covalent binding that is confined primarily to the liver. Each drug exhibited a distinct target profile that, in certain cases, showed strong enrichment for specific metabolic pathways (e.g., lipid/sterol pathways for troglitazone). Site-specific proteomics revealed that acetaminophen reacts with high stoichiometry with several conserved, functional (seleno)cysteine residues throughout the liver proteome. The authors’ findings thus provide an advanced exptl. framework to characterize the proteomic reactivity of drug metabolites in vivo, revealing target profiles that may help to explain mechanisms and identify risk factors for drug-induced liver injury.

ACS Chemical Biology published new progress about Apoptosis. 40180-04-9 belongs to class benzothiophene, name is 2-(2,3-Dichloro-4-(thiophene-2-carbonyl)phenoxy)acetic acid, and the molecular formula is C13H8Cl2O4S, Synthetic Route of 40180-04-9.

Referemce:
Benzothiophene – Wikipedia,
Benzothiophene | C8H6S – PubChem

Wu, Qihui published the artcileIn silico identification and mechanism exploration of hepatotoxic ingredients in traditional Chinese medicine, Name: 2-(2,3-Dichloro-4-(thiophene-2-carbonyl)phenoxy)acetic acid, the main research area is hepatotoxic ingredient traditional Chinese medicine; consensus model; hepatotoxicity mechanism; herb induced liver injury; in silico; traditional chinese medicine.

Backgrounds and Aims: Recently, a growing number of hepatotoxicity cases aroused by Traditional Chinese Medicine (TCM) have been reported, causing increasing concern. To date, the reported predictive models for drug induced liver injury show low prediction accuracy and there are still no related reports for hepatotoxicity evaluation of TCM systematically. Addnl., the mechanism of herb induced liver injury (HILI) still remains unknown. The aim of the study was to identify potential hepatotoxic ingredients in TCM and explore the mol. mechanism of TCM against HILI. Materials and Methods: In this study, we developed consensus models for HILI prediction by integrating the best single classifiers. The consensus model with best performance was applied to identify the potential hepatotoxic ingredients from the Traditional Chinese Medicine Systems Pharmacol. database (TCMSP). Systems pharmacol. analyses, including multiple network construction and KEGG pathway enrichment, were performed to further explore the hepatotoxicity mechanism of TCM. Results: 16 single classifiers were built by combining four machine learning methods with four different sets of fingerprints. After systematic evaluation, the best four single classifiers were selected, which achieved a Matthews correlation coefficient (MCC) value of 0.702, 0.691, 0.659, and 0.717, resp. To improve the predictive capacity of single models, consensus prediction method was used to integrate the best four single classifiers. Results showed that the consensus model C-3 (MCC = 0.78) outperformed the four single classifiers and other consensus models. Subsequently, 5,666 potential hepatotoxic compounds were identified by C-3 model. We integrated the top 10 hepatotoxic herbs and discussed the hepatotoxicity mechanism of TCM via systems pharmacol. approach. Finally, Chaihu was selected as the case study for exploring the mol. mechanism of hepatotoxicity. Conclusion: Overall, this study provides a high accurate approach to predict HILI and an in silico perspective into understanding the hepatotoxicity mechanism of TCM, which might facilitate the discovery and development of new drugs.

Frontiers in Pharmacology published new progress about Bupleurum. 40180-04-9 belongs to class benzothiophene, name is 2-(2,3-Dichloro-4-(thiophene-2-carbonyl)phenoxy)acetic acid, and the molecular formula is C13H8Cl2O4S, Name: 2-(2,3-Dichloro-4-(thiophene-2-carbonyl)phenoxy)acetic acid.

Referemce:
Benzothiophene – Wikipedia,
Benzothiophene | C8H6S – PubChem

Zhu, Xiao published the artcileConstruction and analysis of a human hepatotoxicity database suitable for QSAR modeling using post-market safety data, Formula: C13H8Cl2O4S, the main research area is human hepatotoxicity database liver injury; Drug-induced liver injury; Post-market safety; Predictive toxicology; QSAR.

Drug-induced liver injury (DILI) is one of the most common drug-induced adverse events (AEs) leading to life-threatening conditions such as acute liver failure. It has also been recognized as the single most common cause of safety-related post-market withdrawals or warnings. Efforts to develop new predictive methods to assess the likelihood of a drug being a hepatotoxicant have been challenging due to the complexity and idiosyncrasy of clin. manifestations of DILI. The FDA adverse event reporting system (AERS) contains post-market data that depict the morbidity of AEs. Here, we developed a scalable approach to construct a hepatotoxicity database using post-market data for the purpose of quant. structure-activity relation (QSAR) modeling. A set of 2029 unique and modelable drug entities with 13,555 drug-AE combinations was extracted from the AERS database using 37 hepatotoxicity-related query preferred terms (PTs). To determine the optimal classification scheme to partition pos. from neg. drugs, a manually-curated DILI calibration set composed of 105 negatives and 177 positives was developed based on the published literature. The final classification scheme combines hepatotoxicity-related PT data with supporting information that optimize the predictive performance across the calibration set. Data for other toxicol. endpoints related to liver injury such as liver enzyme abnormalities, cholestasis, and bile duct disorders, were also extracted and classified. Collectively, these datasets can be used to generate a battery of QSAR models that assess a drug’s potential to cause DILI.

Toxicology published new progress about Databases. 40180-04-9 belongs to class benzothiophene, name is 2-(2,3-Dichloro-4-(thiophene-2-carbonyl)phenoxy)acetic acid, and the molecular formula is C13H8Cl2O4S, Formula: C13H8Cl2O4S.

Referemce:
Benzothiophene – Wikipedia,
Benzothiophene | C8H6S – PubChem

Koen, Yakov M. published the artcileIdentification of Protein Targets of Reactive Metabolites of Tienilic Acid in Human Hepatocytes, Related Products of benzothiophene, the main research area is tienilic acid reactive metabolite hepatotoxicity protein target.

Tienilic acid (TA) is a uricosuric diuretic that was withdrawn from the market only months after its introduction because of reports of serious incidents of drug-induced liver injury including some fatalities. Its hepatotoxicity is considered to be primarily immunoallergic in nature. Like other thiophene compounds, TA undergoes biotransformation to a S-oxide metabolite which then reacts covalently with cellular proteins. To identify protein targets of TA metabolites, we incubated [14C]-TA with human hepatocytes, separated cellular proteins by 2D gel electrophoresis, and analyzed proteins in 36 radioactive spots by tryptic digestion followed by LC-MS/MS. Thirty-one spots contained at least one identifiable protein. Sixteen spots contained only one of 14 nonredundant proteins which were thus considered to be targets of TA metabolites. Six of the 14 were also found in other radioactive spots that contained from 1 to 3 addnl. proteins. Eight of the 14 had not been reported to be targets for any reactive metabolite other than TA. The other 15 spots each contained from 2 to 4 identifiable proteins, many of which are known targets of other chem. reactive metabolites, but since adducted peptides were not observed, the identity of the adducted protein(s) in these spots is ambiguous. Interestingly, all the radioactive spots corresponded to proteins of low abundance, while many highly abundant proteins in the mixture showed no radioactivity. Furthermore, of approx. 16 previously reported protein targets of TA in rat liver, only one (fumarylacetoacetase) is among the 14 targets identified in this work. One reason for this difference may be statistical, given that each study identified a small number of targets from among thousands present in hepatocytes. Another may be the species difference (i.e., rat vs human), and still another may be the method of detection of adducted proteins (i.e., Western blot vs C-14). Knowledge of human target proteins is very limited. Of more than 350 known protein targets of reactive metabolites, only 42 are known from humans, and only 21 of these are known to be targets for more than one chem. Nevertheless, the demonstration that human target proteins can be identified using isolated hepatocytes in vitro should enable the question of species differences to be addressed more fully in the future.

Chemical Research in Toxicology published new progress about Diuretics. 40180-04-9 belongs to class benzothiophene, name is 2-(2,3-Dichloro-4-(thiophene-2-carbonyl)phenoxy)acetic acid, and the molecular formula is C13H8Cl2O4S, Related Products of benzothiophene.

Referemce:
Benzothiophene – Wikipedia,
Benzothiophene | C8H6S – PubChem