Regulation of drug transporter mRNA expression by interferon-γ in primary human hepatocytes.
Interferon (IFN)-γ is known to downregulate expression of drug detoxifying proteins such as cytochromes P-450 (CYPs) in human hepatocytes. The present study was designed to determine whether IFN-γ may also impair expression of influx and efflux drug transporters, which constitute important determinants of the liver detoxification pathway. Exposure of primary human hepatocytes to 10 ng/mL IFN-γ was found to downregulate mRNA levels of sinusoidal influx transporters such as sodium-taurocholate cotransporting polypeptide, organic anion transporting polypeptide (OATP) 2B1, OATP1B1, and OATP1B3. IFN-γ concomitantly reduced mRNA expression of drug efflux pumps such as multidrug resistance gene 1, multidrug resistance protein (MRP) 2, MRP3, breast cancer resistance protein and bile salt export pump. Such IFN-γ-mediated repression of major hepatic drug transporters may contribute to impaired liver clearance of drugs administrated to patients suffering from inflammation or viral infections associated with increased secretion of IFN-γ.
Le Vee
Marc
M
EA 4427 Signalisation et Réponse aux Agents Infectieux et Chimiques, Institut de Recherches en Santé Environnement Travail, Université de Rennes 1, Rennes, France.
Jouan
Elodie
E
Moreau
Amélie
A
Fardel
Olivier
O
D000328:Adult; D002478:Cells, Cultured; D015536:Down-Regulation / Q000187:drug effects*; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000150:complications; D007371:Interferon-gamma / Q000378:metabolism / Q000494:pharmacology*; D026901:Membrane Transport Proteins / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D000089762:Multidrug Resistance-Associated Protein 2; D012333:RNA, Messenger / Q000378:metabolism; D014777:Virus Diseases / Q000150:complications
C000715087:ABCC2 protein, human; D026901:Membrane Transport Proteins; D000089762:Multidrug Resistance-Associated Protein 2; D012333:RNA, Messenger; D007371:Interferon-gamma