scholarly journals Effect of prototypical inducers on ligand activated nuclear receptor regulated drug disposition genes in rodent hepatic and intestinal cells

2010 ◽  
Vol 31 (1) ◽  
pp. 51-65 ◽  
Author(s):  
Philip Martin ◽  
Robert Riley ◽  
Paul Thompson ◽  
Dominic Williams ◽  
David Back ◽  
...  
Keyword(s):  
Nuclear Receptor ◽  
Drug Disposition ◽  
Intestinal Cells ◽  
Disposition Genes

scholarly journals Time-Resolved Effect of Interferon-Alpha 2a on Activities of Nuclear Factor Kappa B, Pregnane X Receptor and on Drug Disposition Genes

Pharmaceutics ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 808
Author(s):  
Dirk Theile ◽  
Lelia Wagner ◽  
Cindy Bay ◽  
Walter Emil Haefeli ◽  
Johanna Weiss
Keyword(s):  
Mrna Expression ◽  
Interferon Alpha ◽  
Nuclear Factor Kappa B ◽  
Drug Disposition ◽  
Pregnane X Receptor ◽  
Nuclear Factor ◽  
Cyp3a4 Activity ◽  
Time Resolved ◽  
Nuclear Factor Kappa ◽  
Disposition Genes

Interferon-alpha (IFN-α) is suggested to cause pharmacokinetic drug interactions by lowering expression of drug disposition genes through affecting the activities of nuclear factor kappa B (NF-ĸB) and pregnane X receptor (PXR). The time-resolved impact of IFN-α 2a (1000 U/mL; 5000 U/mL; 2 h to 30 h) on the activities of NF-ĸB and PXR and mRNA expression (5000 U/mL; 24 h, 48 h) of selected drug disposition genes and on cytochrome P450 (CYP3A4) activity in LS180 cells (5000 U/mL; 24 h, 48 h) was evaluated using luciferase-based reporter gene assays, reverse transcription polymerase chain reaction, and luminescence-based CYP3A4 activity assays. The cross-talk between NF-ĸB activation and PXR suppression was evaluated by NF-ĸB blockage (10 µM parthenolide). IFN-α 2a initially (2 h, 6 h) enhanced NF-ĸB activity 2-fold and suppressed PXR activity by 30%. mRNA of CYP3A4 was halved, whereas UGT1A1 was increased (1.35-fold) after 24 h. After 48 h, ABCB1 expression was increased (1.76-fold). CYP3A4 activity remained unchanged after 24 h, but was enhanced after 48 h (1.35-fold). IFN-α 2a demonstrated short-term suppressive effects on PXR activity and CYP3A4 mRNA expression, likely mediated by activated NF-ĸB. Longer exposure enhanced CYP3A4 activity. Clinical trials should evaluate the relevance by investigating the temporal effects of IFN-α on CYP3A4 using a sensitive marker substrate.

scholarly journals From mRNA Expression of Drug Disposition Genes to In Vivo Assessment of CYP-Mediated Biotransformation during Zebrafish Embryonic and Larval Development

2018 ◽  
Vol 19 (12) ◽  
pp. 3976 ◽  
Author(s):  
Evy Verbueken ◽  
Chloé Bars ◽  
Jonathan S. Ball ◽  
Jelena Periz-Stanacev ◽  
Waleed F. A. Marei ◽  
...  
Keyword(s):  
Mrna Expression ◽  
Drug Disposition ◽  
Developmental Toxicity ◽  
Toxicity Testing ◽  
Specific Substrate ◽  
Uridine Diphosphate ◽  
Maternal Metabolism ◽  
Full Capacity ◽  
Disposition Genes

The zebrafish (Danio rerio) embryo is currently explored as an alternative for developmental toxicity testing. As maternal metabolism is lacking in this model, knowledge of the disposition of xenobiotics during zebrafish organogenesis is pivotal in order to correctly interpret the outcome of teratogenicity assays. Therefore, the aim of this study was to assess cytochrome P450 (CYP) activity in zebrafish embryos and larvae until 14 d post-fertilization (dpf) by using a non-specific CYP substrate, i.e., benzyloxy-methyl-resorufin (BOMR) and a CYP1-specific substrate, i.e., 7-ethoxyresorufin (ER). Moreover, the constitutive mRNA expression of CYP1A, CYP1B1, CYP1C1, CYP1C2, CYP2K6, CYP3A65, CYP3C1, phase II enzymes uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) and sulfotransferase 1st1 (SULT1ST1), and an ATP-binding cassette (ABC) drug transporter, i.e., abcb4, was assessed during zebrafish development until 32 dpf by means of quantitative PCR (qPCR). The present study showed that trancripts and/or the activity of these proteins involved in disposition of xenobiotics are generally low to undetectable before 72 h post-fertilization (hpf), which has to be taken into account in teratogenicity testing. Full capacity appears to be reached by the end of organogenesis (i.e., 120 hpf), although CYP1—except CYP1A—and SULT1ST1 were shown to be already mature in early embryonic development.

scholarly journals Dissecting the Effect of Genetic Variation on the Hepatic Expression of Drug Disposition Genes across the Collaborative Cross Mouse Strains

2016 ◽  
Vol 7 ◽  
Author(s):  
Aharon Nachshon ◽  
Hanifa J. Abu-Toamih Atamni ◽  
Yael Steuerman ◽  
Roa'a Sheikh-Hamed ◽  
Alexandra Dorman ◽  
...  
Keyword(s):  
Genetic Variation ◽  
Drug Disposition ◽  
Collaborative Cross ◽  
Mouse Strains ◽  
Hepatic Expression ◽  
Disposition Genes

Iron-induced expression of BMP6 in intestinal cells is the main regulator of hepatic hepcidin expression in vivo

2010 ◽  
Vol 48 (01) ◽  
Author(s):  
S Arndt ◽  
U Mägdefrau ◽  
C Dorn ◽  
K Schardt ◽  
AK Bosserhoff ◽  
...  
Keyword(s):  
Intestinal Cells ◽  
Induced Expression ◽  
Hepcidin Expression ◽  
Main Regulator
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