Hepatocytes

Publication Title: 
American Journal of Physiology. Gastrointestinal and Liver Physiology

Aquaporin 11 (AQP11) is a protein channel expressed intracellularly in multiple organs, yet its physiological function is unclear. Aqp11 knockout (KO) mice die early due to malfunction of the kidney, a result of hydropic degeneration of proximal tubule cells. Here we report the generation of liver-specific Aqp11 KO mice, allowing us to study the role of AQP11 protein in liver of mice with normal kidney function. The unchallenged liver-specific Aqp11 KO mice have normal longevity, their livers appeared normal, and the plasma biochemistries revealed only a minor defect in lipid handling.

Author(s): 
Rojek, Aleksandra
F¸chtbauer, Ernst-Martin
F¸chtbauer, Annette
Jelen, Sabina
Malmendal, Anders
Fenton, Robert A.
Nielsen, S¯ren
Publication Title: 
Stem Cell Reports

Induced pluripotent stem cells (iPSCs) provide an inexhaustible source of cells for modeling disease and testing drugs. Here we develop a bioinformatic approach to detect differences between the genomic programs of iPSCs derived from diseased versus normal human cohorts as they emerge during in†vitro directed differentiation. Using iPSCs generated from a cohort carrying mutations (PiZZ) in the gene responsible for alpha-1 antitrypsin (AAT) deficiency, we find that the global transcriptomes of PiZZ iPSCs diverge from normal controls upon differentiation to hepatic cells.

Author(s): 
Wilson, Andrew A.
Ying, Lei
Liesa, Marc
Segeritz, Charis-Patricia
Mills, Jason A.
Shen, Steven S.
Jean, Jyhchang
Lonza, Geordie C.
Liberti, Derek C.
Lang, Alex H.
Nazaire, Jean
Gower, Adam C.
M¸eller, Franz-Josef
Mehta, Pankaj
OrdÛÒez, Adriana
Lomas, David A.
Vallier, Ludovic
Murphy, George J.
Mostoslavsky, Gustavo
Spira, Avrum
Shirihai, Orian S.
Ramirez, Maria I.
Gadue, Paul
Kotton, Darrell N.
Publication Title: 
Molecular Pharmacology

Artemisinin drugs are of utmost importance in the treatment of malaria, because they represent the sole class of therapeutically used antimalarial drugs to which malaria parasites have not yet developed resistance. The major disadvantage of these medicines is the comparatively high recrudescence rate, which has been attributed to the remarkable decrease of artemisinin plasma concentrations during multiple dosing. Autoinduction of CYP2B6-mediated metabolism has been implicated as the underlying mechanism. So far, the molecular mechanism of induction by artemisinin has not been resolved.

Author(s): 
Burk, Oliver
Arnold, Katja A.
Nüssler, Andreas K.
Schaeffeler, Elke
Efimova, Ekaterina
Avery, Bonnie A.
Avery, Mitchell A.
Fromm, Martin F.
Eichelbaum, Michel
Publication Title: 
Drug Metabolism and Disposition: The Biological Fate of Chemicals

Fa2N-4 cells have been proposed as a tool to identify CYP3A4 inducers. To evaluate whether Fa2N-4 cells are a reliable surrogate for cryopreserved human hepatocytes, we assessed the basal mRNA expression of 64 drug disposition genes in Fa2N-4 cells. Significant differences were found in the expression of major drug-metabolizing enzymes, nuclear receptors, and transporters between both cell types.

Author(s): 
Hariparsad, Niresh
Carr, Brian A.
Evers, Raymond
Chu, Xiaoyan
Publication Title: 
Food and Chemical Toxicology: An International Journal Published for the British Industrial Biological Research Association

Artesunate is a derivate of artemisinin that is both an antimalarial agent and acts cytotoxically on tumor cells. Despite its therapeutic use, its in vivo genotoxic potential has still not been evaluated. This study, therefore, was an investigation into the effects of a single oral administration of artesunate with an in vivo comet assay that analyzed leukocytes from peripheral blood and liver cells, and a micronucleus (MN) assay of bone marrow cells from male Swiss mice. The artesunate was administered by oral gavage at doses of 5, 50 and 100 mg/kg.

Author(s): 
Aquino, Ivani
Perazzo, Fábio Ferreira
Maistro, Edson Luis
Publication Title: 
Proceedings of the National Academy of Sciences of the United States of America

There is an urgent need for new antimalarial drugs with novel mechanisms of action to deliver effective control and eradication programs. Parasite resistance to all existing antimalarial classes, including the artemisinins, has been reported during their clinical use. A failure to generate new antimalarials with novel mechanisms of action that circumvent the current resistance challenges will contribute to a resurgence in the disease which would represent a global health emergency.

Author(s): 
Biagini, Giancarlo A.
Fisher, Nicholas
Shone, Alison E.
Mubaraki, Murad A.
Srivastava, Abhishek
Hill, Alisdair
Antoine, Thomas
Warman, Ashley J.
Davies, Jill
Pidathala, Chandrakala
Amewu, Richard K.
Leung, Suet C.
Sharma, Raman
Gibbons, Peter
Hong, David W.
Pacorel, Bénédicte
Lawrenson, Alexandre S.
Charoensutthivarakul, Sitthivut
Taylor, Lee
Berger, Olivier
Mbekeani, Alison
Stocks, Paul A.
Nixon, Gemma L.
Chadwick, James
Hemingway, Janet
Delves, Michael J.
Sinden, Robert E.
Zeeman, Anne-Marie
Kocken, Clemens H. M.
Berry, Neil G.
O'Neill, Paul M.
Ward, Stephen A.
Publication Title: 
British Journal of Pharmacology

BACKGROUND AND PURPOSE: Widespread resistance to antimalarial drugs requires combination therapies with increasing risk of pharmacokinetic drug-drug interactions. Here, we explore the capacity of antimalarial drugs to induce drug metabolism via activation of constitutive androstane receptors (CAR) by ligand binding. EXPERIMENTAL APPROACH: A total of 21 selected antimalarials and 11 major metabolites were screened for binding to CAR isoforms using cellular and in vitro CAR-coactivator interaction assays, combined with in silico molecular docking.

Author(s): 
Burk, O.
Piedade, R.
Ghebreghiorghis, L.
Fait, J. T.
Nussler, A. K.
Gil, J. P.
Windshügel, B.
Schwab, M.
Publication Title: 
Drug Metabolism and Disposition: The Biological Fate of Chemicals

Artemisinin drugs have become the first-line antimalarials in areas of multidrug resistance. However, monotherapy with artemisinin drugs results in comparatively high recrudescence rates. Autoinduction of cytochrome P450 (P450)-mediated metabolism, resulting in reduced exposure, has been supposed to be the underlying mechanism.

Author(s): 
Xing, Jie
Kirby, Brian J.
Whittington, Dale
Wan, Yakun
Goodlett, David R.
Publication Title: 
PloS One

Acute stress affects cellular integrity in many tissues including the liver, but its underlying mechanism is still unclear. The aim of the present study was to investigate the potential involvement of catecholamines and adrenoceptors in the regulation of acute restraint stress-induced liver injury. Restraint was achieved by placing mice in restraint tubes.

Author(s): 
Zhu, Qing
Gu, Liwei
Wang, Yimei
Jia, Li
Zhao, Zengming
Peng, Shuangqing
Lei, Linsheng
Publication Title: 
Antimicrobial Agents and Chemotherapy

Malaria patients are frequently coinfected with HIV and mycobacteria causing tuberculosis, which increases the use of coadministered drugs and thereby enhances the risk of pharmacokinetic drug-drug interactions. Activation of the pregnane X receptor (PXR) by xenobiotics, which include many drugs, induces drug metabolism and transport, thereby resulting in possible attenuation or loss of the therapeutic responses to the drugs being coadministered. While several artemisinin-type antimalarial drugs have been shown to activate PXR, data on nonartemisinin-type antimalarials are still missing.

Author(s): 
Piedade, Rita
Traub, Stefanie
Bitter, Andreas
Nüssler, Andreas K.
Gil, José P.
Schwab, Matthias
Burk, Oliver

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