Premium
Effects of prototypical nuclear receptor ligands on the expression of enzymes and transporters in primary human hepatocytes
Author(s) -
Ullrich Anett,
Keiser Markus,
Sauer Anne,
Runge Dieter,
Siegmund Werner,
Oswald Stefan
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.257.9
Subject(s) - pregnane x receptor , constitutive androstane receptor , multidrug resistance associated protein 2 , cyp2b6 , cyp3a4 , transporter , abcg2 , enzyme , drug metabolism , pharmacology , biochemistry , atp binding cassette transporter , biology , receptor , chemistry , nuclear receptor , gene , cytochrome p450 , transcription factor
Carbamazepin (Carb), efavirenz (Efa), and rifampicin (Rifa) are known to cause substantial drug‐drug interactions by induction of metabolizing enzymes and transporter proteins via activation of pregnane × and/or constitutive androstane nuclear receptors (PXR and CAR). In order to provide a comprehensive overview about the complex induction pattern of hepatic metabolizing enzymes and transporter proteins, we investigated the effects of the aforementioned substances in primary human hepatocytes. Whole‐transcript arrays with isolated mRNA from hepatocytes were performed with an Affimetrix GeneChip® after incubation with 0.1% DMSO (control), 10 μM Efa or Rifa or 250 μM Carb, respectively. Expression of 42 regulated genes of metabolism and transport were measured using a TaqMan® low density array. All compounds demonstrated inductive effects on the metabolizing enzymes CYP2B6, CYP2C8, CYP3A4, CYP3A5 and CYP3A7 but showed suppressive effects on CYP2E1. ABCB1 and ABCB4 were induced by Efa and ABCC5 and SLC47A1 by Carb. ABCC2, ABCC4 and ABCG2 were induced by both substances. The expression of ATP dependent efflux transporters with the exception of ABCB11 were increased after incubation with all tested drugs. Carb, Efa and Rifa showed strong effects on the expression of several metabolizing enzymes and drug transporters which might be the reason for clinically observed drug‐drug interactions.