Abstract
Tumor necrosis factor (TNF)-α 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-α 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-α and IL-6 concomitantly reduced NTCP and OATP1B1 protein expression and NTCP, OATP, and OCT1 transport activities. IL-6, but not TNF-α, 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-α, 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-α and IL-6. Taken together, these data show that TNF-α 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.
Footnotes
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Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
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doi:10.1124/dmd.108.023630.
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ABBREVIATIONS: LPS, lipopolysaccharide; SLC, solute carrier; NTCP, sodium-taurocholate cotransporting polypeptide; OATP, organic anion-transporting polypeptide; OCT, organic cation transporter; ABC, ATP binding cassette; MDR, multidrug resistance; BSEP, bile salt export pump; MRP, multidrug resistance-associated protein; IL, interleukin; TNF-α, tumor necrosis factor-α; TEA, tetra-ethylammonium; BCRP, breast cancer resistance protein; RT-qPCR, reverse transcription-quantitative polymerase chain reaction; CRP, C-reactive protein; OAT, organic anion transporter.
- Received July 31, 2008.
- Accepted December 12, 2008.
- The American Society for Pharmacology and Experimental Therapeutics
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