Quick Search:

uzh logo
Browse by:
bullet
bullet
bullet
bullet

Zurich Open Repository and Archive

Permanent URL to this publication: http://dx.doi.org/10.5167/uzh-17563

Vee, M L; Lecureur, V; Stieger, B; Fardel, O (2009). Regulation of drug transporter expression in human hepatocytes exposed to the proinflammatory cytokines tumor necrosis factor-alpha or interleukin-6. Drug Metabolism and Disposition, 37(3):685-693.

[img]Accepted Version
PDF - Registered users only
285kB

View at publisher
[img] PDF - Registered users only
484kB

Abstract

Tumor necrosis factor (TNF)-alpha and interleukin (IL)-6 are proinflammatory cytokines known to alter expression of drug transporters in rodent liver. However, their effects toward human hepatic transporters remain poorly characterized. Therefore, this study was designed to analyze the effects of these cytokines on drug transporter expression in primary human hepatocytes. Exposure to 100 ng/ml TNF-alpha or 10 ng/ml IL-6 for 48 h was found to down-regulate mRNA levels of major sinusoidal influx transporters, including sodium-taurocholate cotransporting polypeptide (NTCP), organic anion-transporting polypeptide (OATP) 1B1, OATP1B3, OATP2B1, organic cation transporter (OCT) 1, and organic anion transporter 2. TNF-alpha and IL-6 concomitantly reduced NTCP and OATP1B1 protein expression and NTCP, OATP, and OCT1 transport activities. IL-6, but not TNF-alpha, was also found to decrease mRNA expression of the canalicular transporters multidrug resistance 1 gene, multidrug resistance gene-associated protein (MRP) 2, and breast cancer resistance protein (BCRP); it concomitantly decreased MRP2 and BCRP protein expression. TNF-alpha, unlike IL-6, markedly reduced bile salt export pump mRNA levels and increased BCRP protein expression. Expression of the sinusoidal MRP3 efflux pump was found to be up-regulated at protein level by both TNF-alpha and IL-6. Taken together, these data show that TNF-alpha and IL-6 similarly altered expression of sinusoidal drug transporters and rather differentially that of canalicular efflux transporters. Such pronounced changes in hepatic transporter expression are likely to contribute to both cholestasis and alterations of pharmacokinetics caused by inflammation in humans.

Citations

23 citations in Web of Science®
74 citations in Scopus®
Google Scholar™

Altmetrics

Downloads

0 downloads since deposited on 30 Mar 2009
0 downloads since 12 months

Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Clinic for Clinical Pharmacology and Toxicology
DDC:610 Medicine & health
Language:English
Date:2009
Deposited On:30 Mar 2009 09:39
Last Modified:11 Jul 2014 13:50
Publisher:American Society for Pharmacology and Experimental Therapeutics
ISSN:0090-9556
Publisher DOI:10.1124/dmd.108.023630
PubMed ID:19074973

Users (please log in): suggest update or correction for this item

Repository Staff Only: item control page