24,802 results match your criteria liver microsomal


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Drug Metab Dispos 2021 May 12. Epub 2021 May 12.

Systems Pharmacology, Manchester Pharmacy School, University of Manchester, United Kingdom

linked with physiologically based pharmacokinetic (PBPK) modelling is used to predict the fates of drugs in patients. Ideally, the IVIVE-PBPK models should incorporate "systems" information accounting for characteristics of the specific target population. There is a paucity of such scaling factors in cancer, particularly microsomal protein per gram of liver (MPPGL) and cytosolic protein per gram of liver (CPPGL). Read More

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Structure-based modification of pyrazolone derivatives to inhibit mTORC1 by targeting the leucyl-tRNA synthetase-RagD interaction.

Bioorg Chem 2021 Apr 20;112:104907. Epub 2021 Apr 20.

Department of Integrated OMICS for Biomedical Sciences (WCU Program), Yonsei University, Seoul 03722, Republic of Korea; Department of Biotechnology, Yonsei University, Seoul 03722, Republic of Korea; Department of pharmacy, College of Pharmacy, Yonsei University, Incheon 21983, Republic of Korea. Electronic address:

The enzyme leucyl-tRNA synthetase (LRS) and the amino acid leucine regulate the mechanistic target of rapamycin (mTOR) signaling pathway. Leucine-dependent mTORC1 activation depends on GTPase activating protein events mediated by LRS. In a prior study, compound BC-LI-0186 was discovered and shown to interfere with the mTORC1 signaling pathway by inhibiting the LRS-RagD interaction. Read More

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Design, synthesis and biological evaluation of novel benzofuran derivatives as potent LSD1 inhibitors.

Eur J Med Chem 2021 Apr 24;220:113501. Epub 2021 Apr 24.

Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang, 110016, Liaoning, China.

Lysine-specific demethylase 1 (LSD1) is a FAD-dependent enzyme, which has been proposed as a promising target for therapeutic cancer. Herein, a series of benzofuran derivatives were designed, synthesized and biochemical evaluated as novel LSD1 inhibitors based on scaffold hopping and conformational restriction strategy. Most of the compounds potently suppressed the enzymatic activities of LSD1 and potently inhibited tumor cells proliferation. Read More

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Pathophysiological role of prostaglandin E synthases in liver diseases.

Prostaglandins Other Lipid Mediat 2021 Apr 27;154:106552. Epub 2021 Apr 27.

Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, Jiangsu, 221004, People's Republic of China. Electronic address:

Prostaglandin E synthases (PGESs) convert cyclooxygenase (COX)-derived prostaglandin H (PGH) into prostaglandin E (PGE) and comprise at least three types of structurally and biologically distinct enzymes. Two of these, namely microsomal prostaglandin E synthase-1 (mPGES-1) and mPGES-2, are membrane-bound enzymes. mPGES-1 is an inflammation-inducible enzyme that converts PGH into PGE. Read More

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Impact of , , , and Gene Polymorphisms on the Severity of Liver Fibrosis Induced by HCV Genotype 4.

Viruses 2021 04 20;13(4). Epub 2021 Apr 20.

Department of Microbiology and Immunology, Faculty of Pharmaceutical Sciences and Pharmaceutical Industries, Future University in Egypt, Cairo 11835, Egypt.

Complications of hepatitis C virus (HCV) chronic infection cause ~400,000 deaths worldwide annually. One complication, liver fibrosis, is influenced by host genetic factors. Genes influencing fibrosis include immune, metabolic, oxidative stress, and viral entry genes, such as interleukin 10 (), microsomal triglyceride-transfer protein (), superoxide dismutase-2 (), and apolipoprotein E ()-encoding genes, respectively. Read More

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Polymorphisms in xenobiotic metabolism-related genes in patients with hepatocellular carcinoma: a case-control study.

Xenobiotica 2021 Jun 26;51(6):737-744. Epub 2021 Apr 26.

Molecular Biology Department, Genetics and Molecular Biology Research Unit - UPGEM, São José do Rio Preto Medical School - FAMERP, São Jose do Rio Preto, Brazil.

This study was performed to investigate the relationship between polymorphisms in microsomal epoxide hydrolase (; Tyr113His and His139Arg substitution) and glutathione S-transferase (; deletion, deletion, and .Ala114Val substitution) and their correlation with clinico-histopathological features in hepatocellular carcinoma (HCC).We evaluated environmental risk factors and genetic alterations in 556 individuals (86 cases and 470 controls). Read More

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Determination and structural characterization of ravidasvir metabolites by liquid chromatography coupled to triple quadrupole linear ion trap mass spectrometry: Application to pharmacokinetics and phase I metabolism in rats.

Biomed Chromatogr 2021 Apr 24:e5146. Epub 2021 Apr 24.

Center of Excellence for Preclinical Research in Drug Development, City of Scientific Research and Technological Applications, New Borg El-Arab, Alexandria, Egypt.

Infectious disease such as hepatitis C virus (HCV) is a global clinical issue because of its significant morbidity and mortality. Novel anti-hepatitis C drugs are continuously developed to decrease the pervasiveness of the infection around the world. A synthetic ravidasvir, benzimidazole-naphthylene-imidazole derivatives, has been used as an anti-HCV drug. Read More

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Metabolic Activation of Aegeline Mediated by CYP2C19.

Xenobiotica 2021 Apr 23:1-38. Epub 2021 Apr 23.

Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang, Liaoning 110016, P. R. China.

1. Aegeline (AGL) is a natural alkaloidal amide mainly isolated from the leaves and fruits of tropical plant , with multiple pharmacological activities.2. Read More

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Adiponectin involved in portal flow hepatic extraction of 13C-metacethin in obesity and non-alcoholic fatty liver.

Eur J Intern Med 2021 Apr 15. Epub 2021 Apr 15.

Clinica Medica "A. Murri", Department of Biomedical Sciences and Human Oncology, University of Bari Aldo Moro, Bari 70124, Italy. Electronic address:

Obesity and non-alcoholic fatty liver disease (NAFLD) are high prevalence, inter-related conditions at increased risk for advanced liver diseases and related mortality. Adiponectin and leptin have divergent roles in the pathogenesis of fat accumulation and NAFLD. However, the relationships between body and liver fat accumulation, early modification of liver function and unbalanced adipokine levels are still scarcely explored. Read More

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Targeting Chikungunya Virus Replication by Benzoannulene Inhibitors.

J Med Chem 2021 Apr 9;64(8):4762-4786. Epub 2021 Apr 9.

Drug Discovery Division, Southern Research, 2000 Ninth Avenue South, Birmingham, Alabama 35205, United States.

A benzo[6]annulene, 4-(-butyl)--(3-methoxy-5,6,7,8-tetrahydronaphthalen-2-yl) benzamide (), was identified as an inhibitor against Chikungunya virus (CHIKV) with antiviral activity EC = 1.45 μM and viral titer reduction (VTR) of 2.5 log at 10 μM with no observed cytotoxicity (CC = 169 μM) in normal human dermal fibroblast cells. Read More

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Homozygous Familial Hypercholesterolemia (HoFH) in Saudi Arabia and Two Cases of Lomitapide Use in a Real-World Setting.

Adv Ther 2021 May 7;38(5):2159-2169. Epub 2021 Apr 7.

College of Medicine, King Saud Bin Abdulaziz University for Health Sciences, Jeddah, Saudi Arabia.

Introduction: Homozygous familial hypercholesterolemia (HoFH) is a rare, genetic condition in which mutations in key peptides involved in the low-density lipoprotein receptor (LDL-R) pathway result in markedly elevated levels of circulating LDL-cholesterol (LDL-C). Patients are at high risk of developing early-onset atherosclerotic cardiovascular disease with associated mortality risks. Treatment options are extremely limited, and aspects of society and medical care in Saudi Arabia have the potential to increase incidence and limit treatment pathways in HoFH. Read More

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Design, Synthesis and Characterization of HIV-1 CA-Targeting Small Molecules: Conformational Restriction of PF74.

Viruses 2021 03 15;13(3). Epub 2021 Mar 15.

Center for Drug Design, College of Pharmacy, University of Minnesota, Minneapolis, MN 55455, USA.

Small molecules targeting the PF74 binding site of the HIV-1 capsid protein (CA) confer potent and mechanistically unique antiviral activities. Structural modifications of PF74 could further the understanding of ligand binding modes, diversify ligand chemical classes, and allow identification of new variants with balanced antiviral activity and metabolic stability. In the current work, we designed and synthesized three series of PF74-like analogs featuring conformational constraints at the aniline terminus or the phenylalanine carboxamide moiety, and characterized them using a biophysical thermal shift assay (TSA), cell-based antiviral and cytotoxicity assays, and in vitro metabolic stability assays in human and mouse liver microsomes. Read More

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Species Differences in Microsomal Metabolism of Xanthine-Derived A Adenosine Receptor Ligands.

Pharmaceuticals (Basel) 2021 Mar 18;14(3). Epub 2021 Mar 18.

Institute of Neuroscience and Medicine-Nuclear Chemistry (INM-5), Forschungszentrum Jülich GmbH, 52428 Jülich, Germany.

Tracer development for positron emission tomography (PET) requires thorough evaluation of pharmacokinetics, metabolism, and dosimetry of candidate radioligands in preclinical animal studies. Since variations in pharmacokinetics and metabolism of a compound occur in different species, careful selection of a suitable model species is mandatory to obtain valid data. This study focuses on species differences in the in vitro metabolism of three xanthine-derived ligands for the A adenosine receptor (AAR), which, in their F-labeled form, can be used to image AAR via PET. Read More

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Ultrasensitive quantification of drug-metabolizing enzymes and transporters in small sample volume by microflow LC-MS/MS.

J Pharm Sci 2021 Mar 28. Epub 2021 Mar 28.

Department of Pharmaceutical Sciences, Washington State University, 12 E Spokane Falls Blvd, Spokane, WA 99202, USA. Electronic address:

Protein abundance data of drug-metabolizing enzymes and transporters (DMETs) are broadly applicable to the characterization of in vitro and in vivo models, in vitro to in vivo extrapolation (IVIVE), and interindividual variability prediction. However, the emerging need of DMET quantification in small sample volumes such as organ-on a chip effluent, organoids, and biopsies requires ultrasensitive protein quantification methods. We present an ultrasensitive method that relies on an optimized sample preparation approach involving acetone precipitation coupled with a microflow-based liquid chromatography-tandem mass spectrometry (µLC-MS/MS) for the DMET quantification using limited sample volume or protein concentration, i. Read More

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Ibuprofen alters epoxide hydrolase activity and epoxy-oxylipin metabolites associated with different metabolic pathways in murine livers.

Sci Rep 2021 Mar 29;11(1):7042. Epub 2021 Mar 29.

Department of Neurobiology, Physiology, and Behavior, University of California, Davis, CA, 95616, USA.

Over the last decade oxylipins have become more recognized for their involvement in several diseases. Non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen are known to inhibit cyclooxygenase (COX) enzymes, but how NSAIDs affect oxylipins, in addition to COX products, in animal tissues is not well understood. Oxylipins in livers from male and female mice treated with 100 mg/kg/day of ibuprofen for 7 days were investigated. Read More

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Novel PF74-like small molecules targeting the HIV-1 capsid protein: Balance of potency and metabolic stability.

Acta Pharm Sin B 2021 Mar 31;11(3):810-822. Epub 2020 Jul 31.

Center for Drug Design, College of Pharmacy, University of Minnesota, Minneapolis, MN 55455, USA.

Of all known small molecules targeting human immunodeficiency virus (HIV) capsid protein (CA), PF74 represents by far the best characterized chemotype, due to its ability to confer antiviral phenotypes in both early and late phases of viral replication. However, the prohibitively low metabolic stability renders PF74 a poor antiviral lead. We report herein our medicinal chemistry efforts toward identifying novel and metabolically stable small molecules targeting the PF74 binding site. Read More

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Discovery of N-amido-phenylsulfonamide derivatives as novel microsomal prostaglandin E synthase-1 (mPGES-1) inhibitors.

Bioorg Med Chem Lett 2021 Jun 26;41:127992. Epub 2021 Mar 26.

Research Institute for Basic Sciences and Department of Chemistry, College of Sciences, Kyung Hee University, Seoul 02447, Republic of Korea; KHU-KIST Department of Converging Science and Technology, Kyung Hee University, Seoul 02447, Republic of Korea. Electronic address:

Our previous research showed that N-carboxy-phenylsulfonyl hydrazide (scaffold A) could reduce LPS-stimulated PGE levels in RAW 264.7 macrophage cells by an inhibition of mPGES-1 enzyme. However, a number of scaffold A derivatives showed the drawbacks such as the formation of regioisomers and poor liver metabolic stability. Read More

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Glycogen Hepatopathy: A Reversible yet Relapsing Cause of Hepatitis in Type 1 Diabetics.

Cureus 2021 Feb 19;13(2):e13441. Epub 2021 Feb 19.

Gastroenterology, Bethesda Hospital East, Boynton Beach, USA.

Glycogen hepatopathy (GH), a rare glycogen storage disease caused by genetic or acquired overactivation of hepatic glycogen synthesis enzymes, can mimic non-alcoholic fatty liver disease (NAFLD). We describe a case of biopsy-proven GH in an adult with type 1 diabetes mellitus (DM). A 33-year-old Honduran woman with a 25-year history of type 1 DM complicated by gastroparesis, multiple episodes of diabetic ketoacidosis (DKA) and hypoglycemia, and recurrent pancreatitis was referred for abnormal liver enzymes. Read More

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February 2021

[Influence of the L-carnitine and resveratrol complex on physiological, biochemical and morphological indicators of normal and obese rats].

Vopr Pitan 2021;90(1):15-32. Epub 2021 Jan 20.

Federal Research Centre of Nutrition, Biotechnology and Food Safety, 109240, Moscow, Russian Federation.

Specialized products and dietary supplements, enriched with complexes of minor biologically active substances (BAS), are often offered as components of therapeutic diets in the treatment of obesity and metabolic syndrome. At the same time, the possible effects of the interactions of BAS when consuming a multicomponent product have not been studied enough. - to study the action on rats' organism of a complex supplement (RС), containing resveratrol (Res) and L-carnitine (L-Car), when consumed with a standard balanced or hypercaloric diet. Read More

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January 2021

Application of niclosamide and analogs as small molecule inhibitors of Zika virus and SARS-CoV-2 infection.

Bioorg Med Chem Lett 2021 05 6;40:127906. Epub 2021 Mar 6.

National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Bethesda, MD 20892-3370, USA. Electronic address:

Zika virus has emerged as a potential threat to human health globally. A previous drug repurposing screen identified the approved anthelminthic drug niclosamide as a small molecule inhibitor of Zika virus infection. However, as antihelminthic drugs are generally designed to have low absorption when dosed orally, the very limited bioavailability of niclosamide will likely hinder its potential direct repurposing as an antiviral medication. Read More

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Spectrophotometric Assessment of Heme Oxygenase-1 Activity in -infected Macrophages.

Bio Protoc 2020 Apr 5;10(7):e3578. Epub 2020 Apr 5.

Department of Biochemistry, University of Calcutta, Kolkata, India.

Heme oxygenase-1 (HO-1) is a stress responsive enzyme that metabolizes heme and releases free iron, carbon monoxide (CO), and biliverdin (BV), which rapidly undergoes conversion to bilirubin (BL). Estimation of bilirubin is the basis of HO-1 assay. HO-1 activity is widely employed to determine antioxidant response of cells under different physiological stress environment. Read More

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ENZYMATIC ACTIVITY IN MICROSOMES, LIPID PEROXIDATION OF MICE HEPATOCYTES UNDER THE SODIUM FLUORIDE.

Georgian Med News 2021 Jan(310):169-176

The State Institution "Lugansk State Medical University", Rubizhne, Ukraine.

Fluorine is one of the most widespread and necessary microelements for the body of animals and humans, which is necessary in a clearly limited amount. Different concentrations of fluorine can affect the state of lipid peroxidation, as well as the functional state of the microsomes of liver hepatocytes. The studies were carried out on mature Wistar rats weighing 180-220 g. Read More

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January 2021

In vitro and in silico studies of interaction of synthetic 2,6,9-trisubstituted purine kinase inhibitors BPA-302, BP-21 and BP-117 with liver drug-metabolizing cytochromes P450

Physiol Res 2020 12;69(Suppl 4):S627-S636

Department of Pharmacology, Faculty of Medicine, Palacký University Olomouc, Czech Republic.

An evaluation of possible interactions with enzymes of drug metabolism (cytochromes P450, CYP) is an important part of studies on safety and, in general, on the properties of any drug or biologically active compound. The article is focused on the preliminary metabolic study of selected 2,6,9-trisubstituted purine kinase inhibitors with significant anticancer activities which we have developed. The compounds BP-21 and BP-117 represent strong CDK inhibitors and the compound BPA-302 was developed as selective FLT3-ITD kinase inhibitor. Read More

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December 2020

Deficiency of Nardilysin in the Liver Reduces Serum Cholesterol Levels.

Biol Pharm Bull 2021 ;44(3):363-371

Division of Clinical Pharmacy, Faculty of Pharmaceutical Sciences, Kobe Gakuin University.

Nardilysin (NRDC) has been shown to be involved in post-translational histone modifications, in addition to enhancement in ectodomain shedding of membrane-anchored protein, which play significant roles in various pathophysiology, including glucose homeostasis, inflammatory diseases and cancer. The present study sought to determine roles of NRDC in the liver on lipid and lipoprotein metabolism. We established liver-specific NRDC deficient mice by use of NRD1 floxed mice and albumin promoter-Cre recombinase (Cre) transgenic mice, and found that their serum low-density lipoprotein (LDL) cholesterol levels were significantly lower than those in control littermate mice. Read More

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January 2021

Liver specific deletion of mouse Tm6sf2 promotes steatosis, fibrosis and hepatocellular cancer.

Hepatology 2021 Feb 27. Epub 2021 Feb 27.

Department of Medicine, Washington University School of Medicine, St. Louis, MO, 63110, United States.

Background And Aims: Human TM6SF2 variant rs58542926 is associated with nonalcoholic fatty liver disease (NAFLD) and hepatocellular cancer (HCC). However, conflicting reports in germline Tm6sf2 knockout mice suggest no change or decreased VLDL secretion and either unchanged or increased hepatic steatosis, with no increased fibrosis. We generated liver specific Tm6Sf2 knockout mice (Tm6 LKO) to study VLDL secretion and the impact on development and progression of NAFLD. Read More

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February 2021

DNA Sequence Modulates the Efficiency of NEIL1-Catalyzed Excision of the Aflatoxin B-Induced Formamidopyrimidine Guanine Adduct.

Chem Res Toxicol 2021 Mar 17;34(3):901-911. Epub 2021 Feb 17.

Oregon Institute of Occupational Health Sciences, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, Oregon 97239, United States.

Dietary exposure to aflatoxins is a significant risk factor in the development of hepatocellular carcinomas. Following bioactivation by microsomal P450s, the reaction of aflatoxin B (AFB) with guanine (Gua) in DNA leads to the formation of stable, imidazole ring-opened 8,9-dihydro-8-(2,6-diamino-4-oxo-3,4-dihydropyrimid-5-yl-formamido)-9-hydroxyaflatoxin B (AFB-FapyGua) adducts. In contrast to most base modifications that result in destabilization of the DNA duplex, the AFB-FapyGua adduct increases the thermal stability of DNA via 5'-interface intercalation and base-stacking interactions. Read More

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Discovery of 3-(4-(2-((1-Indol-5-yl)amino)-5-fluoropyrimidin-4-yl)-1-pyrazol-1-yl)propanenitrile Derivatives as Selective TYK2 Inhibitors for the Treatment of Inflammatory Bowel Disease.

J Med Chem 2021 02 16;64(4):1966-1988. Epub 2021 Feb 16.

State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital of Sichuan University, Chengdu 610041, China.

TYK2 mediates signaling of IL-23, IL-12, and Type I IFN-driven responses that are critical in immune-mediated diseases. Herein, we report the design, synthesis, and structure-activity relationships (SARs) of 3-(4-(2-((1-indol-5-yl)amino)-5-fluoropyrimidin-4-yl)-1-pyrazol-1-yl)propanenitrile derivatives as selective TYK2 inhibitors. Among them, compound exhibited acceptable TYK2 inhibition with an IC value of 9 nM, showed satisfactory selectivity characteristics over the other three homologous JAK kinases, and performed good functional potency in the JAK/STAT signaling pathway on lymphocyte lines and human whole blood. Read More

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February 2021

Magnesium accumulation upon cyclin M4 silencing activates microsomal triglyceride transfer protein improving NASH.

J Hepatol 2021 Feb 9. Epub 2021 Feb 9.

Liver Disease Laboratory, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, Derio, Spain.

Background & Aims: Perturbations of intracellular magnesium (Mg) homeostasis have implications for cell physiology. The cyclin M family, CNNM, perform key functions in the transport of Mg across cell membranes. Herein, we aimed to elucidate the role of CNNM4 in the development of non-alcoholic steatohepatitis (NASH). Read More

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February 2021

Evaluation of Tissue Binding in Three Tissues across Five Species and Prediction of Volume of Distribution from Plasma Protein and Tissue Binding with an Existing Model.

Drug Metab Dispos 2021 Apr 2;49(4):330-336. Epub 2021 Feb 2.

Drug Metabolism and Pharmacokinetics, Genentech, Inc., South San Francisco, California

Volume of distribution (V) is a primary pharmacokinetic parameter used to calculate the half-life and plasma concentration-time profile of drugs. Numerous models have been relatively successful in predicting V, but the model developed by Korzekwa and Nagar is of particular interest because it utilizes plasma protein binding and microsomal binding data, both of which are readily available in vitro parameters. Here, Korzekwa and Nagar's model was validated and expanded upon using external and internal data sets. Read More

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High-resolution mass spectrometry-based approach for the identification and profiling of the metabolites of taletrectinib formed in liver microsomes.

Drug Test Anal 2021 Feb 1. Epub 2021 Feb 1.

Department of Hematology, Zhongshan Hospital of Sun Yat-Sen University & Zhongshan City People's Hospital, Zhongshan, China.

Taletrectinib is a potent, orally active, and selective ROS1/NTRK kinase inhibitor. The aim of this study was to study the metabolism of taletrectinib in rat, dog, and human liver microsomes. The biotransformation of taletrectinib was carried out using rat, dog, and human liver microsomes supplemented with nicotinamide adenine dinucleotide phosphate tetrasodium salt (NADPH) and uridine diphosphate glucuronic acid (UDPGA). Read More

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February 2021