Category: 40180-04-9

Poli-Scaife, Sonia published the artcileThe Substrate Binding Site of Human Liver Cytochrome P450 2C9: An NMR Study, Quality Control of 40180-04-9, the main research area is substrate binding cytochrome P450 2C9 NMR; inhibitor binding cytochrome P450 2C9 NMR; sulfaphenazole binding cytochrome P450 2C9 NMR.

Purified recombinant human liver cytochrome P 450 2C9 was produced, from expression of the corresponding cDNA in yeast, in quantities large enough for UV-visible and 1H NMR experiments Its interaction with several substrates (tienilic acid and two derivatives, lauric acid and diclofenac) and with a specific inhibitor, sulfaphenazole, was studied by UV-visible and 1H NMR spectroscopy. At 27°, all those substrates led to an almost complete conversion of CYP 2C9 to high-spin (S = 5/2) CYP 2C9-substrate complexes characterized by a Soret peak at 390 nm; their KD values varied between 1 and 42 μM. On the contrary, sulfaphenazole led to a low-spin (S = 1/2) CYP 2C9 complex upon binding of its NH2 group to CYP 2C9 iron. Interactions of the five substrates with the enzyme were studied by paramagnetic relaxation effects of CYP 2C9-iron(III) on the 1H NMR spectrum of each substrate. Distances between the heme iron atom and substrate protons were calculated from the NMR data, and the orientation of the substrate relative to iron was determined from those distances. Finally, a model for substrate positioning in the CYP 2C9 active site was constructed by mol. modeling studies under the constraint of the iron-proton distances. It points out two structural characteristics for a compound to be selectively recognized by CYP 2C9: (i) the presence of an anionic site able to establish an ionic bond with a putative cationic residue of the protein and (ii) the presence of an hydrophobic zone between the substrate hydroxylation site and the anionic site. Sulfaphenazole was easily included in that model; its very high affinity for CYP 2C9 is due to a third structural feature, the presence of its NH2 function which binds to CYP 2C9 iron.

Biochemistry published new progress about Enzyme functional sites, active. 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

Rademacher, Peter M. published the artcileDifferential Oxidation of Two Thiophene-Containing Regioisomers to Reactive Metabolites by Cytochrome P450 2C9, HPLC of Formula: 40180-04-9, the main research area is oxidation thiophene regioisomer metabolite cytochrome P450 2C9.

The uricosuric diuretic agent tienilic acid (TA) is a thiophene-containing compound that is metabolized by P 450 2C9 to 5-OH-TA. A reactive metabolite of TA also forms a covalent adduct to P 450 2C9 that inactivates the enzyme and initiates immune-mediated hepatic injury in humans, purportedly through a thiophene-S-oxide intermediate. The 3-thenoyl regioisomer of TA, tienilic acid isomer (TAI), is chem. very similar and is reported to be oxidized by P 450 2C9 to a thiophene-S-oxide, yet it is not a mechanism-based inactivator (MBI) of P 450 2C9 and is reported to be an intrinsic hepatotoxin in rats. The goal of the work presented in this article was to identify the reactive metabolites of TA and TAI by the characterization of products derived from P 450 2C9-mediated oxidation In addition, in silico approaches were used to better understand both the mechanisms of oxidation of TA and TAI and/or the structural rearrangements of oxidized thiophene compounds Incubation of TA with P 450 2C9 and NADPH yielded the well-characterized 5-OH-TA metabolite as the major product. However, contrary to previous reports, it was found that TAI was oxidized to two different types of reactive intermediates that ultimately lead to two types of products, a pair of hydroxythiophene/thiolactone tautomers and an S-oxide dimer. Both TA and TAI incorporated 18O from 18O2 into their resp. hydroxythiophene/thiolactone metabolites indicating that these products are derived from an arene oxide pathway. Intrinsic reaction coordinate calculations of the rearrangement reactions of the model compound 2-acetylthiophene-S-oxide showed that a 1,5-oxygen migration mechanism is energetically unfavorable and does not yield the 5-OH product but instead yields a six-membered oxathiine ring. Therefore, arene oxide formation and subsequent NIH-shift rearrangement remains the favored mechanism for formation of 5-OH-TA. This also implicates the arene oxide as the initiating factor in TA induced liver injury via covalent modification of P 450 2C9. Finally, in silico modeling of P 450 2C9 active site ligand interactions with TA using the catalytically active iron-oxo species revealed significant differences in the orientations of TA and TAI in the active site, which correlated well with exptl. results showing that TA was oxidized only to a ring carbon hydroxylated product, whereas TAI formed both ring carbon hydroxylated products and an S-oxide.

Chemical Research in Toxicology published new progress about Enzyme functional sites, active. 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

Lecoeur, Sylvaine published the artcileSpecificity of in vitro Covalent Binding of Tienilic Acid Metabolites to Human Liver Microsomes in Relationship to the Type of Hepatotoxicity: Comparison with Two Directly Hepatotoxic Drugs, Name: 2-(2,3-Dichloro-4-(thiophene-2-carbonyl)phenoxy)acetic acid, the main research area is tienilate metabolite binding liver microsome hepatotoxicity; cytochrome P4502C9 tienilate binding antibody formation.

To better understand the first steps leading to drug-induced immunoallergic hepatitis, the authors studied the target of anti-LKM2 autoantibodies appearing in tienilic acid-induced hepatitis, and the target of tienilic acid-reactive metabolites. It was identified as cytochrome P 450 2C9, (P 450 2C9): indeed,anti-LKM2 specifically recognized P 450 2C9, but none of the other P450s tested (including other 2C subfamily members, 2C8 and 2C18). Tienilic acid-reactive metabolite(s) specifically bound to P 4502C9, and experiments with yeast expressing active isolated P450s showed that P 450 2C9 was responsible for tienilic acid-reactive metabolite(s) production Results of qual. and quant. covalent binding of tienilic acid metabolite(s) to human liver microsomes were then compared to those obtained with two drugs leading to direct toxic hepatitis, namely, acetaminophen and chloroform. Kinetic constants (Km and Vmax) were measured, and the covalent binding profile of the metabolites to human liver microsomal proteins was studied. Tienilic acid had both the lowest Km and the highest covalent binding rate at pharmacol. doses. For acetaminophen and chloroform, several microsomal proteins were covalently bound, while covalent binding was highly specific for tienilic acid and dihydralazine, another drug leading to immunoallergic hepatitis. Although low numbers of drugs were tested, these results led the authors to think that there may exist a relation between the specificity of covalent binding and the type of hepatotoxicity.

Chemical Research in Toxicology published new progress about Autoantibodies, monoclonal Role: BIOL (Biological Study). 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

Sellman, R. published the artcileInduction of microsomal epoxide hydrolase by tienilic acid in the rat, Application In Synthesis of 40180-04-9, the main research area is tienilic acid microsome epoxide hydrolase.

The effects of tienilic acid (I) [40180-04-9] on drug-metabolizing enzymes in rat liver and kidneys were studied. Short-term treatment for 2 wk (450 mg/kg/day) increased the activity of microsomal epoxide hydrolase  [9048-63-9] at least 2-fold in both rat liver and kidneys. The effect of tienilic acid on the activity of microsomal epoxide hydrolase in the liver was correlated with the dose at 20-450 mg/kg/day for 14 days. Tienilic acid had only marginal effects on cytochrome P-450-mediated monooxygenases. Tienilic acid caused an approx. 2-fold increase in glucuronide conjugation of 4-methylumbelliferone in the liver. No increase in the activity of rat hepatic microsomal UDP-glucuronosyltransferase toward o-aminophenol was detected. According to these results, tienilic acid can be regarded as one of the most specific inducers of microsomal epoxide hydrolase.

Journal of Applied Toxicology published new progress about Drug-metabolizing enzymes Role: PROC (Process). 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 In Synthesis of 40180-04-9.

Referemce:
Benzothiophene – Wikipedia,
Benzothiophene | C8H6S – PubChem

Beaune, Philippe published the artcileAutoantibodies to cytochrome P-450 during autoimmune hepatitis, Related Products of benzothiophene, the main research area is tienilic acid hepatitis autoantibody cytochrome P450; liver kidney microsome autoantibody drug hepatitis; autoimmune hepatitis autoantibody cytochrome.

Anti-liver/kidney microsomes (anti-LKM) autoantibodies have been found in the serum of patients suffering from different kinds of hepatitis including tienilic acid-induced hepatitis. These autoantibodies were used to study the nature of the macromol. that they recognized. By using immunoblot and immunoinhibition techniques it was shown that these autoantibodies recognized specifically human cytochrome P 450-8 (= P-450 MP or P 450-II C9); this cytochrome P-450 is also responsible for the oxidation of tienilic acid and mephenytoin and produced a reactive metabolite covalently bound to proteins. A simple scheme describing some of the steps leading to the disease is proposed. The study of other autoantibodies seems to show that the scheme which is proposed is rather general.

Colloque INSERM published new progress about Autoantibodies Role: BIOL (Biological Study). 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

Beaune, P. published the artcileHuman anti-endoplasmic reticulum autoantibodies appearing in a drug-induced hepatitis are directed against a human liver cytochrome P-450 that hydroxylates the drug, Quality Control of 40180-04-9, the main research area is cytochrome P450 autoantibody drug hepatitis.

Anti-liver/kidney microsome (anti-LKM) autoantibodies were found in the serum of patients with cryptogenic chronic hepatitis and with immunoallergic drug-induced hepatitis, such as those induced by halothane or by tienilic acid (called anti-LKM2 in this case). So far the nature of the human microsomal macromols. recognized by these antibodies has not been determined Here it is shown, by using immunoblot techniques, that among the macromols. present in human adult liver microsomes, one protein called cytochrome P 450-8 is specifically recognized by most sera of patients containing anti-LKM2 antibodies but not by control serum. Human fetal liver microsomes that do not contain cytochrome P 450-8 are not recognized by the anti-LKM2 antibodies. It is also shown that anti-cytochrome P 450-8 antibodies as well as human serum containing anti-LKM2 antibodies specifically inhibit the hydroxylation of tienilic acid by human liver microsomes. These results indicate that anti-LKM2 antibodies appearing in patients with hepatitis and concomitant administration of tienilic acid are directed against a cytochrome P 450 isoenzyme that catalyzes the metabolic oxidation of this drug. This suggests a possible mechanism for the appearance of anti-organelle antibodies in a drug-induced hepatitis.

Proceedings of the National Academy of Sciences of the United States of America published new progress about Autoantibodies Role: BIOL (Biological Study). 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

Hsiao, Ya-Wen published the artcileA Pragmatic Approach Using First-Principle Methods to Address Site of Metabolism with Implications for Reactive Metabolite Formation, Recommanded Product: 2-(2,3-Dichloro-4-(thiophene-2-carbonyl)phenoxy)acetic acid, the main research area is drug metabolism reactive metabolite formation.

A majority of xenobiotics are metabolized by cytochrome P 450 (CYP) enzymes. The discovery of drug candidates with low propensity to form reactive metabolites and low clearance can be facilitated by understanding CYP-mediated xenobiotic metabolism Being able to predict the sites where reactive metabolites form is beneficial in drug design to produce drug candidates free of reactive metabolite issues. Herein, we report a pragmatic protocol using first-principle d. functional theory (DFT) calculations for predicting sites of epoxidation and hydroxylation of aromatic substrates mediated by CYP. The method is based on the relative stabilities of the CYP-substrate intermediates or the substrate epoxides. Consequently, it concerns mainly the electronic reactivity of the substrates. Comparing to the exptl. findings, the presented protocol gave excellent first-ranked epoxidation site predictions of 83%, and when the test was extended to CYP-mediated sites of aromatic hydroxylation, satisfactory results were also obtained (73%). This indicates that our assumptions are valid and also implies that the intrinsic reactivities of the substrates are in general more important than their binding poses in proteins, although the protocol may benefit from the addition of docking information.

Journal of Chemical Information and Modeling published new progress about Aflatoxins Role: PKT (Pharmacokinetics), BIOL (Biological Study). 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, Recommanded Product: 2-(2,3-Dichloro-4-(thiophene-2-carbonyl)phenoxy)acetic acid.

Referemce:
Benzothiophene – Wikipedia,
Benzothiophene | C8H6S – PubChem

Jinno, Norimasa published the artcileContribution of cytochrome P450 and UDT-glucuronosyltransferase to the metabolism of drugs containing carboxylic acid groups: risk assessment of acylglucuronides using human hepatocytes, Product Details of C13H8Cl2O4S, the main research area is cytochrome P450 UGT inhibitor metabolism acylglucuronide risk assessment hepatocyte; (�-borneol; 1-aminobenzotriazole; UDP-glucuronosyltransferase; acylglucuronide; cytochrome P450; human hepatocyte.

1. In order to evaluate the inhibition activity of 1-aminobenzotriazole (ABT) and (-)-borneol (borneol) against cytochrome P 450 (CYP) and UDP-glucuronosyltransferase (UGT), the substrates of these metabolic enzymes were incubated with ABT and borneol in human hepatocytes. We found that 3 mM ABT and 300 μM borneol were the most suitable exptl. levels to specifically inhibit CYP and UGT. 2. Montelukast, mefenamic acid, flufenamic acid, diclofenac, tienilic acid, gemfibrozil, ibufenac and repaglinide were markedly metabolized in human hepatocytes, and the metabolism of gemfibrozil, mefenamic acid and flufenamic acid was inhibited by borneol. With regard to repaglinide, montelukast, diclofenac and tienilic acid, metabolism was inhibited by ABT. Ibufenac was partly inhibited by both inhibitors. Zomepirac, tolmetin, ibuprofen, indomethacin and levofloxacin were moderately metabolized by human hepatocytes, and the metabolism of zomepirac, ibuprofen and indomethacin was equally inhibited by both ABT and borneol. The metabolism of tolmetin was strongly inhibited by ABT, and was also inhibited weakly by borneol. Residual drugs, telmisartan, valsartan, furosemide, naproxen and probenecid were scarcely metabolized. 3. Although we attempted to predict the toxicol. risks of drugs containing carboxylic groups from the combination chem. stability and CLint via UGT, the results indicated that this combination was not sufficient and that clin. daily dose is important.

Xenobiotica published new progress about Carboxylic acids Role: BSU (Biological Study, Unclassified), BIOL (Biological Study). 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

Liu, Yitong published the artcileAnthraquinones inhibit cytochromes P450 enzyme activity in silico and in vitro, COA of Formula: C13H8Cl2O4S, the main research area is anthraquinone cytochrome enzyme activity human liver microsome; QSAR; aloe-emodin; anthraquinone; cytochrome P450 enzyme; emodin; human liver microsome; human recombinant enzyme; inhibition; rhein.

Anthraquinones exhibit various pharmacol. activities (e.g., antioxidant and laxative) and are commonly found in consumer products including foods, dietary supplements, drugs, and traditional medicines. Despite their widespread use, there are limited data available on their toxicokinetic properties. Cytochrome P 450 enzymes (CYPs) in the liver play major roles in metabolizing exogenous chems. (e.g., pharmaceuticals, food ingredients, and environmental pollutants) and endogenous biomols. (e.g., steroid hormones and cholesterol). Inhibition of CYP activities may lead to serious interactions among these compounds Here, in silico (quant. structure-activity relationship modeling) and in vitro (human recombinant enzymes and liver microsomes) methods were used to identify inhibitors of five major CYP isoforms (CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4) among 22 anthraquinones. First, in silico prediction and in vitro human recombinant enzyme assays were conducted for all compounds, and results showed that most of the anthraquinones were potent CYP1A2 inhibitors. Second, five selected anthraquinones (emodin, aloe-emodin, rhein, purpurin, and rubiadin) were further evaluated in human liver microsomes. Finally, plasma concentrations of the five anthraquinones in animal and humans were identified in the literature and compared to their in vitro inhibition potency (IC50 values) towards CYP activities. Emodin, rhein, and aloe-emodin inhibited activities of multiple CYPs in human liver microsomes and potential in vivo inhibition may occur due to their high plasma concentrations These in silico and in vitro results enabled rapid identification of potential CYP inhibitors and prioritized future in-depth studies.

Journal of Applied Toxicology published new progress about Anthraquinones Role: BSU (Biological Study, Unclassified), BIOL (Biological Study). 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, COA of Formula: C13H8Cl2O4S.

Referemce:
Benzothiophene – Wikipedia,
Benzothiophene | C8H6S – PubChem

Manns, Michael P. published the artcileRecent developments in autoimmune liver diseases, Category: benzothiophene, the main research area is review autoimmune liver disease.

A review with 141 references Several diseases are regarded as autoimmune liver diseases. Apart from the cholestatic liver diseases, primary biliary cirrhosis, primary sclerosing cholangitis, these include autoimmune hepatitis, hepatitis as part of the autoimmune polyendocrine syndrome type 1 (APS-1) and particular overlap syndromes such as autoimmune cholangitis (also called anti-mitochondrial antibody neg. primary biliary cirrhosis [PBC]), overlap syndrome chronic active hepatitis (CAH)/PBC and the overlap syndrome primary sclerosing hepatitis (PSC)/CAH. In addition, auto-antibodies may be observed during the course of chronic viral hepatitis, in particular chronic hepatitis C and D. Finally, a small number of drug-induced liver diseases is immune mediated. The author also discusses recent progress in the field of autoimmune hepatitis including APS-1 and autoimmunity in viral hepatitis and immune-mediated drug-induced liver disease.

Journal of Gastroenterology and Hepatology published new progress about Autoantibodies Role: BSU (Biological Study, Unclassified), BIOL (Biological Study). 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, Category: benzothiophene.

Referemce:
Benzothiophene – Wikipedia,
Benzothiophene | C8H6S – PubChem