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Search results for: UGT1A6

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#36293566   2022/10/21 To Up

The Mutation Hotspots at UGT1A Locus May Be Associated with Gilbert's Syndrome Affecting the Taiwanese Population.

Gilbert's syndrome is mainly diagnosed through genetic analysis and is primarily detected through a mutation in the promoter region of the gene. However, most of the research has been conducted on Caucasian populations. In this study, we studied the Han population in Taiwan to investigate the possibility of other mutations that could cause Gilbert's syndrome. This study comprised a test group of 45 Taiwanese individuals with Gilbert's syndrome and 180 healthy Taiwanese individuals as a control group. We extracted DNA from the blood samples and then used Axiom Genome-Wide TWB 2.0 array plates for genotyping. Out of 302,771 single nucleotide polymorphisms (SNPs) from 225 subjects, we detected 57 SNPs with the most significant shift in allele frequency; 27 SNPs among them were located in the UGT1A region. Most of the detected SNPs highly correlated with each other and are located near the first exon of , and . We used these SNPs as an input for the machine learning algorithms and developed prediction models. Our study reveals a good association between the 27 SNPs detected and Gilbert's syndrome. Hence, this study provides a reference for diagnosing Gilbert's syndrome in the Taiwanese population in the future.
Paul Wei-Che Hsu, Po-Cheng Liao, Yu-Hsiang Kao, Xin-Yu Lin, Rong-Nan Chien, Chau-Ting Yeh, Chi-Chun Lai, Yu-Chiau Shyu, Chih-Lang Lin

1303 related Products with: The Mutation Hotspots at UGT1A Locus May Be Associated with Gilbert's Syndrome Affecting the Taiwanese Population.

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#36250837   // To Up

Impact of MDR1 and UGT Gene Polymorphisms on Sodium Valproate Plasma Concentration in Patients with Epilepsy.

This study aimed to identify the effects of multidrug resistance gene 1 (MDR1) and UGT gene polymorphisms on the plasma concentration of VPA in subjects with epilepsy and provide a reference for individualized medicine of patients with epilepsy.
Cangsang Song, Xingde Li, Hanshu Zhang, Jinying Bao, Wei Lu, Qingping Peng, Yang Zhang

1733 related Products with: Impact of MDR1 and UGT Gene Polymorphisms on Sodium Valproate Plasma Concentration in Patients with Epilepsy.

50 ml 50 UG100 ml500 ml10ml5ug96T1 mg

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#36000181   2022/08/28 To Up

Changes in uridine 5'-diphospho-glucuronosyltransferase 1A6 expression by histone deacetylase inhibitor valproic acid.

Valproic acid (VPA) is well-known as a histone deacetylase (HDAC) inhibitor. It has been reported that HDAC inhibitors enhance basal and aryl hydrocarbon receptor (AhR) ligand-induced aryl hydrocarbon receptor-responsive gene expression. Other studies suggested that HDAC inhibition might significantly activate the NF-E2-related factor-2 (Nrf2). Moreover, VPA activates mitogen-activated protein kinases (MAPKs). MAPK pathways regulate Nrf2 transactivation domain activity. Uridine 5'-diphospho-glucuronosyltransferase (UGT) 1A6 is one of the important isoforms to affect drug pharmacokinetics. UGT1A6 gene is regulated transcriptionally by AhR and Nrf2. The present study aimed to investigate whether UGT1A6 expression was changed by VPA and to elucidate the mechanism of the alteration. Following VPA treatment for 72 h in Caco-2 cells, UGT1A6 mRNA was increased by 7.9-fold. Moreover, UGT1A6 mRNA was increased by other HDAC inhibitors, suggesting that HDAC inhibition caused the UGT1A6 mRNA induction. AhR and Nrf2 proteins in the nucleus of Caco-2 cells were increased by 1.5- and 1.7-fold, respectively, following the VPA treatment. However, VPA treatment did not activate the extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) pathways in Caco-2 cells. In conclusion, we observed that VPA induced UGT1A6 mRNA expression via AhR and Nrf2 pathways, but not via the ERK or JNK pathways.
Yukiko Sakakibara, Ayaka Kojima, Yuki Asai, Masayuki Nadai, Miki Katoh

1746 related Products with: Changes in uridine 5'-diphospho-glucuronosyltransferase 1A6 expression by histone deacetylase inhibitor valproic acid.

10mg1 g5mg10mg5mg10mg50mg10mg1 ml20 µl (10 mM)96 assays

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#35930428   2022/08/23 To Up

Effects of common genetic variants of human uridine diphosphate glucuronosyltransferase subfamilies on irinotecan glucuronidation.

The adverse effects (diarrhea and neutropenia) of irinotecan (7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin) are associated with genetic variants of uridine diphosphate glucuronosyltransferase 1A subfamilies (s). UGT1As are enzymes that metabolize the active form of irinotecan, 7-ethyl-10 hydroxycamptothecin (SN-38), by glucuronidation in the liver. They are widely known as predictive factors of severe adverse effects, such as neutropenia and diarrhea. Some studies have suggested that variants of s affect SN-38 glucuronidation activities, thus exerting severe adverse effects. We aimed to identify UGT1A isoforms that show SN-38 glucuronidation activity and determine the relationship between variants and SN-38 glucuronidation . We found that UGT1A1 and UGT1A6-UGT1A10 displayed SN-38 glucuronidation activity. Among these, UGT1A1 was the most active. Furthermore, the variants of these isoforms showed decreased SN-38 glucuronidation activity. In our study, we compared the different variants of s, such as , , and , to determine the differences in the reduction of glucuronidation. Our study elucidates the relationship between variants and the level of glucuronidation associated with each variant. Therefore, testing can be done before the initiation of irinotecan treatment to predict potential toxicities and adverse effects.
Kouji Tagawa, Yoshihiro Maruo, Yu Mimura, Shinichi Ikushiro

1327 related Products with: Effects of common genetic variants of human uridine diphosphate glucuronosyltransferase subfamilies on irinotecan glucuronidation.

96T100.00 ug2 100 MG100.00 ug100.00 ug 100ul1 mg 5 G10 μg1 mg10

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#35680134   2022/06/09 To Up

Characterization of JNJ-2482272 [4-(4-Methyl-2-(4-(Trifluoromethyl)Phenyl)Thiazole-5-yl) Pyrimidine-2-Amine] As a Strong Aryl Hydrocarbon Receptor Activator in Rat and Human.

[4-(4-Methyl-2-(4-(trifluoromethyl)phenyl)thiazole-5-yl)pyrimidine-2-amine] (JNJ-2482272), under investigation as an anti-inflammatory agent, was orally administered to rats once daily at 60 mg/kg for 6 consecutive days. Despite high plasma exposure after single administration (C of 7.1 M), JNJ-2482272 had plasma concentrations beneath the lower limit of quantification (3 ng/ml) after 6 consecutive days of dosing. To determine if JNJ-2482272 is an autoinducer in rats, plated rat hepatocytes were treated with JNJ-2482272 for 2 days. The major hydroxylated metabolites of JNJ-2482272 were isolated and characterized by mass spectrometry and NMR analyses. Compared with the vehicle-treated cells, a concentration-dependent increase was observed in the formation of phase I- and II-mediated metabolites coinciding with greater expression of cytochrome P450s (P450s) and UDP-glucuronosyltransferases (UGTs) in rat hepatocytes. CYP1A1, CYP1A2, CYP1B1, and UGT1A6 transcripts were predominantly induced, suggesting that JNJ-2482272 is an activator of the aryl hydrocarbon receptor (AhR). In a human AhR reporter assay, JNJ-2482272 demonstrated potent AhR activation with an EC value of 0.768 nM, a potency more comparable to the strong AhR activator and toxin 2,3,7,8-tetrachloro-dibenzodioxin than to weaker AhR activators 3-methylcholanthrene, -naphthoflavone, and omeprazole. In plated human hepatocytes, JNJ-2482272 induced CYP1A1 gene expression with an EC of 20.4 nM and increased CYP1A activity >50-fold from basal levels. In human recombinant P450s, JNJ-2482272 was exclusively metabolized by the CYP1 family of enzymes and most rapidly by CYP1A1. The summation of these in vitro findings bridges the in vivo conclusion that JNJ-2482272 is a strong autoinducer in rats and potentially in humans through potent AhR activation. SIGNIFICANCE STATEMENT: Drugs that induce their own metabolism (autoinducers) can lack sustained exposures for pharmacology and safety assessment hindering their development. JNJ-2482272 is demonstrated herein as a strong aryl hydrocarbon receptor (AhR) activator and CYP1A autoinducer, explaining its near complete loss of exposure after repeat administration in rat, which is likely translatable to human (if progressed further) considering its nanomolar potency comparable to "classical" AhR ligands like 2,3,7,8-tetrachloro-dibenzo-dioxin despite bearing a "nonclassical" drug structure.
Kevin J Coe, Mark Feinstein, J William Higgins, Perry Leung, Brian P Scott, Judy Skaptason, Yuen Tam, Laurie P Volak, Jennifer Kinong, Anton Bittner, Heather McAllister, Nathan M Lim, Michael Hack, Tatiana Koudriakova

1194 related Products with: Characterization of JNJ-2482272 [4-(4-Methyl-2-(4-(Trifluoromethyl)Phenyl)Thiazole-5-yl) Pyrimidine-2-Amine] As a Strong Aryl Hydrocarbon Receptor Activator in Rat and Human.

100ul50 ug100 μg100 μg100 μg5 mg100 μg1000 100 μg100 μg

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#35629166   2022/05/04 To Up

Association of Genetic Polymorphisms with Complications of Implanted LVAD Devices in Patients with Congestive Heart Failure: A Kazakhstani Study.

The left ventricular assist device (LVAD) is one of the alternative treatments for heart failure (HF) patients. However, LVAD support is followed by thrombosis, and bleeding complications which are caused by high non-physiologic shear stress and antithrombotic/anticoagulant therapy. A high risk of complications occurs in the presence of the genotype polymorphisms which are involved in the coagulation system, hemostasis function and in the metabolism of the therapy. The aim of the study was to investigate the influence of single-nucleotide polymorphisms (SNP) in HF patients with LVAD complications. We analyzed 21 SNPs in HF patients ( = 98) with/without complications, and healthy controls ( = 95). SNPs rs9934438; rs9923231 in , rs5918 in and rs2070959 in demonstrated significant association with HF patients' complications (OR (95% CI): 3.96 (1.42-11.02), = 0.0057), (OR (95% CI): 3.55 (1.28-9.86), = 0.011), (OR (95% CI): 5.37 (1.79-16.16), = 0.0056) and OR (95% CI): 4.40 (1.06-18.20), = 0.044]. Genotype polymorphisms could help to predict complications at pre- and post-LVAD implantation period, which will reduce mortality rate. Our research showed that patients can receive treatment with warfarin and aspirin with a personalized dosage and LVAD complications can be predicted by reference to their genotype polymorphisms in , and genes.
Madina R Zhalbinova, Saule E Rakhimova, Ulan A Kozhamkulov, Gulbanu A Akilzhanova, Galina K Kaussova, Kenes R Akilzhanov, Yuriy V Pya, Joseph H Lee, Makhabbat S Bekbossynova, Ainur R Akilzhanova

2532 related Products with: Association of Genetic Polymorphisms with Complications of Implanted LVAD Devices in Patients with Congestive Heart Failure: A Kazakhstani Study.

100 UG100 μg100μg100 μg100ug100 μg

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#35629143   2022/04/29 To Up

Common Variant Alleles Determine Acetaminophen Pharmacokinetics in Man.

Acetaminophen (paracetamol) is a widely used drug that causes adverse drug events that are often dose-dependent and related to plasma drug concentrations. Acetaminophen metabolism strongly depends on UGT1A enzymes. We aimed to investigate putative factors influencing acetaminophen pharmacokinetics. We analyzed acetaminophen pharmacokinetics after intravenous administration in 186 individuals, and we determined the effect of sex; body mass index (BMI); previous and concomitant therapy with UGT1A substrates, inhibitors, and inducers; as well as common variations in the genes coding for UGT1A1, UGT1A6, and UGT1A9. We identified sex and genetic variants as major factors influencing acetaminophen pharmacokinetics, with women showing lower clearance ( < 0.001) and higher area under the plasma drug concentration-time curve (AUC) values than men ( < 0.001). genetic variants were related to decreased acetaminophen biodisposition. Individuals who were homozygous or double-heterozygous for variant alleles showed a 22.5% increase in t values and a 22.8 increase in drug exposure ( < 0.001, and 0.006, respectively) after correction by sex. The effect is related to the and variant alleles, whereas no effect of and alleles, BMI, or drug-drug interaction was identified in this study. We conclude that sex and variants determine acetaminophen pharmacokinetics, thus providing evidence to eventually developing pharmacogenomics procedures and recommendations for acetaminophen use.
María de Las Olas Cerezo-Arias, Javier Gómez-Tabales, Manuel Martí, Elena García-Martín, José A G Agúndez

1736 related Products with: Common Variant Alleles Determine Acetaminophen Pharmacokinetics in Man.

100ug100 μg11 inhibitors100 μg200 96 tests0.5 mg100ug Lyophilized 25 G

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#35436549   2022/04/15 To Up

Metabolic conjugation reduces in vitro toxicity of the flavonoid nevadensin.

The present study focuses on the association between metabolic capacity and toxicity of the natural occurring flavonoid nevadensin in vitro. Human colon (HT29), liver (HepG2) and bone marrow (KG1) carcinoma cells were used and strong cell line dependent differences in toxic effect strength were found. HepG2 and KG1 cells were more sensitive against nevadensin treatment in comparison to HT29 cells. High resolution mass spectrometry experiments showed that nevadensin is rapidly glucuronidated in HT29 cells, whereas KG1 cells do not metabolize nevadensin, thus glucuronidation was supposed to be a crucial metabolic pathway in vitro. To proof this suggestion, nevadensin glucuronides were isolated from pig liver microsomes und structurally elucidated via NMR spectroscopy. In HepG2 cells a cellular enrichment of nevadensin itself as well as nevadensin-7-O-glucuronide was determined by tandem mass spectrometry. A proteomic screening of uridine 5'-diphospho (UDP)-glucuronosyltransferase (UGT) in HT29 and HepG2 cells provided first hints that the isoforms UGT1A6 and UGT1A1 are responsible for nevadensin glucuronidation. Additionally, nevadensin was found to be a potent SULT inhibitor in HepG2 cells. In sum, the present study clearly illustrates the importance of obtaining detailed information about metabolic competence of cell lines which should be considered in the evaluation of toxic endpoints.
Lena Müller, Lucas Keuter, David Bücksteeg, Thomas Uebel, Markus Wilken, Lina Schürmann, Matthias Behrens, Hans-Ulrich Humpf, Melanie Esselen

2294 related Products with: Metabolic conjugation reduces in vitro toxicity of the flavonoid nevadensin.

10mg500 gm.50 ug1mg

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#35405201   2022/04/08 To Up

Regulation of phase I and phase II neurosteroid enzymes in the hippocampus of an Alzheimer's disease rat model: A focus on sulphotransferases and UDP-glucuronosyltransferases.

Neurosteroids have been associated with neurodegenerative diseases because they are involved in the modulation of neurotransmitter, neurotropic and neuroprotective actions. Emerging evidence suggests that the enzymes responsible for the synthesis of neurosteroids change during the progression of Alzheimer's disease (AD). The present study aimed to assess the changes in phase I and II enzymes involved in the metabolism of neurosteroids of the progestogen, androgenic and estrogenic steroidogenic pathways and the possibility that the neurosteroids are actively converted into the most abundant metabolites (i.e. glucuronides and sulphates). The gene expression for the phase I and II neurosteroid biosynthetic enzymes were studied in the hippocampus of streptozotocin AD rat model. Male Sprague-Dawley rats were randomly divided into control, sham (saline injected into the hippocampus) and 3 and 12 weeks post-STZ administration (STZ-G3w and STZ-G12w, respectively) groups. Behavioral assessments showed memory impairment in both STZ-injected groups, whereas the formation of amyloid-beta was more pronounced in the STZ-12w group. Gene expression of the hippocampus revealed that glucuronidation and sulphation enzymes transcript of the phase I metabolites were upregulated at the late stage of the disease progression (Hsd17b10, Hsd3b1, Akr1c3 and Cyp19a1) except for Sts. The phase II Sult and Ugt enzymes were mostly upregulated in the STZ-G12w rats (Sult1a1, Sult1e1, Ugt1a1, Ugt1a7c, Ugt1a6, Ugt2b35 and Ugt2b17) and normally expressed in the STZ-G3w group (Sult2a2, Sult2a6, Sult2b1, Ugt2b7, Sult4a1 and Ugt1a7c). In conclusion, changes occur in the phase I and II enzymes transcript of the progestogen, androgenic and estrogenic steroidogenic pathways during the progression of AD.
Mazzura Wan Chik, Nurul Aqmar Mohd Nor Hazalin, Gurmeet Kaur Surindar Singh

2604 related Products with: Regulation of phase I and phase II neurosteroid enzymes in the hippocampus of an Alzheimer's disease rat model: A focus on sulphotransferases and UDP-glucuronosyltransferases.

100 UG500 tests96 tests 50 UG500 tests96 tests

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#35370268   // To Up

The Effect of Single-Walled Carbon Nanotubes on UDP-Glucuronosyltransferase 1A Activity in Human Liver.

Single-walled carbon nanotubes (SWCNTs) are made from rolled single graphene sheets with a diameter in the nanometer range and are potential carriers for drug delivery systems. However, their effects on uridine 5'-diphosphate-glucuronosyltransferase (UGT) 1A activities remain unclear. The present study aimed to investigate the effect of two kinds of SWCNTs (EC1.5-P- and FH-P-SWCNTs) and other nanocarbons on human UGT1A activity due to the proposed application of SWCNTs in drug and gene delivery. β-Estradiol 3-glucuronidation, which is catalyzed mainly by UGT1A1, was inhibited by 99 and 76% in the presence of 0.1 mg/mL EC1.5-P- and FH-P-SWCNTs in human liver microsomes, respectively. The observed decrease of free UGT1A1 protein in the enzyme reaction mixture suggests a higher interaction with SWCNTs, and indicates the inhibition of β-estradiol 3-glucuronidation. Imipramine N-glucuronidation, which is formed mainly by UGT1A4, was also decreased by SWCNTs. Serotonin glucuronidation, which is mainly responsible for UGT1A6, was only influenced by specific nanocarbons in human liver microsomes. The attenuation of free UGT1A6 protein was observed with SWCNTs and carbon black, indicating that UGT1A6 activity was not influenced by the direct interaction of SWCNTs. We also observed a 127% increase by FH-P-SWCNTs for propofol glucuronidation in human liver microsomes, which is catalyzed mainly by UGT1A9. The values of maximum velocity and intrinsic clearance for propofol glucuronidation in the presence of FH-P-SWCNT were 1.8- and 2.0-fold higher than those of the control in human liver microsomes. These results suggest that the effects of SWCNTs on UGT1A are different among isoforms.
Yuki Asai, Masayuki Nadai, Miki Katoh

1039 related Products with: The Effect of Single-Walled Carbon Nanotubes on UDP-Glucuronosyltransferase 1A Activity in Human Liver.

900 tests96T1g1 mg 100ul100 μg100 μg100 μg5ug100 μg50 ug

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