scholarly journals Rifampin modulation of xeno- and endobiotic conjugating enzyme mRNA expression and associated microRNAs in human hepatocytes

2018 ◽  
Vol 6 (2) ◽  
pp. e00386 ◽  
Author(s):  
Brandon T. Gufford ◽  
Jason D. Robarge ◽  
Michael T. Eadon ◽  
Hongyu Gao ◽  
Hai Lin ◽  
...  
Keyword(s):  
Mrna Expression ◽  
Human Hepatocytes ◽  
Conjugating Enzyme

scholarly journals Lack of effect of metofluthrin and sodium phenobarbital on replicative DNA synthesis and Ki-67 mRNA expression in cultured human hepatocytes

2015 ◽  
Vol 4 (4) ◽  
pp. 901-913 ◽  
Author(s):  
Tomoya Yamada ◽  
Hiroko Kikumoto ◽  
Brian G. Lake ◽  
Satoshi Kawamura
Keyword(s):  
Dna Synthesis ◽  
Mrna Expression ◽  
Human Hepatocytes ◽  
Ki 67 ◽  
High Doses ◽  
Sodium Phenobarbital

High doses of metofluthrin have been shown to produce hepatocellular tumours in rats.

Use of mRNA expression to detect the induction of drug metabolising enzymes in rat and human hepatocytes

2009 ◽  
Vol 235 (1) ◽  
pp. 86-96 ◽  
Author(s):  
L. Richert ◽  
G. Tuschl ◽  
C. Abadie ◽  
N. Blanchard ◽  
D. Pekthong ◽  
...  
Keyword(s):  
Mrna Expression ◽  
Human Hepatocytes ◽  
Drug Metabolising Enzymes

scholarly journals Expression and hepatobiliary transport characteristics of the concentrative and equilibrative nucleoside transporters in sandwich-cultured human hepatocytes

2008 ◽  
Vol 295 (3) ◽  
pp. G570-G580 ◽  
Author(s):  
Rajgopal Govindarajan ◽  
Christopher J. Endres ◽  
Dale Whittington ◽  
Edward LeCluyse ◽  
Marçal Pastor-Anglada ◽  
...  
Keyword(s):  
Mrna Expression ◽  
Rank Order ◽  
Human Hepatocytes ◽  
Nucleoside Transporters ◽  
Hepatic Tissue ◽  
Cultured Hepatocytes ◽  
Hepatobiliary Transport ◽  
Hepatic Diseases ◽  
Nucleoside Drugs

We previously reported that both the concentrative (hCNT) and equilibrative (hENT) nucleoside transporters are expressed in the human liver ( 21 ). Here we report a study that investigated the expression of these transporters (transcripts and proteins) and their role in the hepatobiliary transport of nucleosides/nucleoside drugs using sandwich-cultured human hepatocytes. In the hepatic tissue, the rank order of the mRNA expression of the transporters was hCNT1 ≈ hENT1 > hENT2 ≈ hCNT2 > hCNT3. In sandwich-cultured hepatocytes, the mRNA expression of hCNT2 and hENT2 was comparable to that in hepatic tissue, whereas the expression of corresponding transporters in the two-dimensional hepatocyte cultures was lower. Colocalization studies demonstrated predominant localization of these transporters at the sinusoidal membrane and of hENT1, hCNT1, and hCNT2 at the canalicular membrane. In the sandwich-cultured hepatocytes, ENTs were the major contributors to the transport of thymidine (hENT1, 63%; hENT2, 23%) or guanosine (hENT1, 53%; hENT2, 24%) into the hepatocytes followed by hCNT1 (10%) for thymidine or hCNT2 (23%) for guanosine. Although ribavirin was predominately transported (89%) into the hepatocytes by hENT1, fialuridine (FIAU) was transported by both hENT1 (30%) and hCNTs (61%). The extensively metabolized natural nucleosides were not effluxed into the bile, whereas significant biliary-efflux was observed of FIAU (19%), ribavirin (30%), and formycin B (35%). We conclude that the hepatic activity of hENT1 and hCNT1/2 transporters will determine the in vivo hepatic distribution and therefore the efficacy and/or toxicity of nucleoside drugs used to treat hepatic diseases.

scholarly journals Mertansine Inhibits mRNA Expression and Enzyme Activities of Cytochrome P450s and Uridine 5′-Diphospho-Glucuronosyltransferases in Human Hepatocytes and Liver Microsomes

Pharmaceutics ◽  
2020 ◽  
Vol 12 (3) ◽  
pp. 220
Author(s):  
Won-Gu Choi ◽  
Ria Park ◽  
Dong Kyun Kim ◽  
Yongho Shin ◽  
Yong-Yeon Cho ◽  
...  
Keyword(s):  
Mrna Expression ◽  
Enzyme Activities ◽  
Human Liver ◽  
Liver Microsomes ◽  
Human Hepatocytes ◽  
Cytochrome P450s ◽  
Human Liver Microsomes ◽  
Mrna Levels ◽  
Tubulin Inhibitor

Mertansine, a tubulin inhibitor, is used as the cytotoxic component of antibody–drug conjugates (ADCs) for cancer therapy. The effects of mertansine on uridine 5′-diphospho-glucuronosyltransferase (UGT) activities in human liver microsomes and its effects on the mRNA expression of cytochrome P450s (CYPs) and UGTs in human hepatocytes were evaluated to assess the potential for drug–drug interactions (DDIs). Mertansine potently inhibited UGT1A1-catalyzed SN-38 glucuronidation, UGT1A3-catalyzed chenodeoxycholic acid 24-acyl-β-glucuronidation, and UGT1A4-catalyzed trifluoperazine N-β-d-glucuronidation, with Ki values of 13.5 µM, 4.3 µM, and 21.2 µM, respectively, but no inhibition of UGT1A6, UGT1A9, and UGT2B7 enzyme activities was observed in human liver microsomes. A 48 h treatment of mertansine (1.25–2500 nM) in human hepatocytes resulted in the dose-dependent suppression of mRNA levels of CYP1A2, CYP2B6, CYP3A4, CYP2C8, CYP2C9, CYP2C19, UGT1A1, and UGT1A9, with IC50 values of 93.7 ± 109.1, 36.8 ± 18.3, 160.6 ± 167.4, 32.1 ± 14.9, 578.4 ± 452.0, 539.5 ± 233.4, 856.7 ± 781.9, and 54.1 ± 29.1 nM, respectively, and decreased the activities of CYP1A2-mediated phenacetin O-deethylase, CYP2B6-mediated bupropion hydroxylase, and CYP3A4-mediated midazolam 1′-hydroxylase. These in vitro DDI potentials of mertansine with CYP1A2, CYP2B6, CYP2C8/9/19, CYP3A4, UGT1A1, and UGT1A9 substrates suggest that it is necessary to carefully characterize the DDI potentials of ADC candidates with mertansine as a payload in the clinic.

Effect of Aflatoxin B1 on Nuclear Receptors PXR, CAR, and AhR and Their Target Cytochromes P450 mRNA Expression in Primary Cultures of Human Hepatocytes

2011 ◽  
Vol 31 (1) ◽  
pp. 86-93 ◽  
Author(s):  
Imen Ayed-Boussema ◽  
Jean-Marc Pascussi ◽  
Patrick Maurel ◽  
Hassen Bacha ◽  
Wafa Hassen
Keyword(s):  
Mrna Expression ◽  
Aflatoxin B1 ◽  
Messenger Rna ◽  
Animal Feed ◽  
Cytochromes P450 ◽  
Primary Cultures ◽  
Constitutive Androstane Receptor ◽  
Pregnane X Receptor ◽  
Receptor Activation ◽  
Human Hepatocytes

Aflatoxin B1 (AFB1), one of the most common mycotoxins found in human foods and animal feed, is principally hepatotoxic and hepatocarcinogenic. The aim of the present study was to explore the effect of AFB1 on messenger RNA (mRNA) expression of pregnane X receptor (PXR), constitutive androstane receptor (CAR), and aryl hydrocarbon receptor (AhR) and some of their target cytochromes using primary cultures of human hepatocytes. Our results showed that AFB1, at noncytotoxic increasing concentrations, caused a significant upregulation of cytochrome P 2B6 (CYP2B6), CYP3A5, and to a lesser extent CYP3A4 and CYP2C9. Pregnane X receptor and CAR mRNA expression increased in the 3 treated livers. Aflatoxin B1 was found also to induce an overexpression of CYP1A1 and CYP1A2 genes accompanied by an increase in AhR mRNA expression. These findings suggest that AFB1 could activate PXR, CAR, and AhR; however, further investigations are needed to confirm nuclear receptor activation by AFB1.

scholarly journals mRNA Expression and Activity of Nucleoside Transporters in Human Hepatoma HepaRG Cells

Pharmaceutics ◽  
2018 ◽  
Vol 10 (4) ◽  
pp. 246
Author(s):  
Abdullah Mayati ◽  
Amélie Moreau ◽  
Elodie Jouan ◽  
Marie Febvre-James ◽  
Claire Denizot ◽  
...  
Keyword(s):  
Mrna Expression ◽  
Cell Line ◽  
Human Hepatocytes ◽  
Nucleoside Transporters ◽  
Nucleoside Transporter ◽  
Human Hepatoma ◽  
Heparg Cell Line ◽  
Heparg Cells ◽  
Pkc Activation ◽  
Expression And Activity

The HepaRG cell line is a highly differentiated human hepatoma cell line, displaying the expression of various drug transporters. However, functional expression of nucleoside transporters remains poorly characterized in HepaRG cells, although these transporters play a key role in hepatic uptake of antiviral and anticancer drugs. The present study was, therefore, designed to characterize the expression, activity and regulation of equilibrative (ENT) and concentrative (CNT) nucleoside transporter isoforms in differentiated HepaRG cells. These cells were found to exhibit a profile of nucleoside transporter mRNAs similar to that found in human hepatocytes, i.e., notable expression of ENT1, ENT2 and CNT1, with very low or no expression of CNT2 and CNT3. ENT1 activity was, next, demonstrated to be the main uridine transport activity present in HepaRG cells, like in cultured human hepatocytes. Various physiological factors, such as protein kinase C (PKC) activation or treatment by inflammatory cytokines or hepatocyte growth factor (HGF), were additionally found to regulate expression of ENT1, ENT2 and CNT1; PKC activation and HGF notably concomitantly induced mRNA expression and activity of ENT1 in HepaRG cells. Overall, these data suggest that HepaRG cells may be useful for analyzing cellular pharmacokinetics of nucleoside-like drugs in human hepatic cells, especially of those handled by ENT1.

Inter-Subject Variability in OCT1 Activity in 27 Batches of Cryopreserved Human Hepatocytes and Association with OCT1 mRNA Expression and Genotype

2017 ◽  
Vol 34 (6) ◽  
pp. 1309-1319 ◽  
Author(s):  
Sarinj Fattah ◽  
Abhijit Babaji Shinde ◽  
Maja Matic ◽  
Myriam Baes ◽  
Ron H. N. van Schaik ◽  
...  
Keyword(s):  
Mrna Expression ◽  
Human Hepatocytes ◽  
Subject Variability

Species differences in hepatocyte induction of CYP1A1 and CYP1A2 by omeprazole

1999 ◽  
Vol 18 (2) ◽  
pp. 95-105 ◽  
Author(s):  
Hsueh Shih ◽  
George V Pickwell ◽  
Denis K Guenette ◽  
Bahri Bilir ◽  
Linda C Quattrochi
Keyword(s):  
Mrna Expression ◽  
Transcriptional Activation ◽  
Species Differences ◽  
Primary Cultures ◽  
Rat Hepatocytes ◽  
Human Hepatocytes ◽  
Gastric Ulcers ◽  
Cyp1a Mrna ◽  
Mouse Hepatocytes ◽  
Human Livers

1 Omeprazole, a proton pump inhibitor therapeutically administered for the treatment of gastric ulcers, induces the expression of cytochromes P4501A1/2 (CYP1A1/2) through transcriptional activation mediated by the Ah (dioxin)-receptor. Primary cultures of hepatocytes isolated from rabbit, rat, mouse and human livers were compared for CYP1A1/2 mRNA inducibility by omeprazole (1 to 100 μM). 2 Primary cultures of human hepatocytes were the most sensitive to the inducing effects of omeprazole. Rabbit hepatocytes were the only other cells studied that showed induced CYP1A1/2 mRNA expression from a concentration lower than 100 μM (i.e., 10 μM). Rat hepatocytes were the least sensitive to omeprazole induction. The response of mouse hepatocytes to omeprazole treatment was variable, with CYP1A1/2 mRNA expression being induced in only two of the three cultures examined. 3 Differences in the time dependence of CYP1A1/2 mRNA expression were observed between species. In general, after treatment of hepatocytes with omeprazole the levels of CYP1A1 mRNA peaked prior to that of CYP1A2 mRNA. 4 Due to the interspecific variability of CYP1A mRNA inducibility by omeprazole, we conclude that human hepatocytes in culture are probably the only appropriate animal model for prediction of CYP1A induction in humans.

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