EA 4427 SeRAIC, Faculté de Pharmacie, Rennes, France.
Expert Opin Drug Metab Toxicol. 2009 Dec;5(12):1469-81. doi: 10.1517/17425250903304056.
Sinuosidal and canalicular hepatic drug transporters, involved in drug uptake in the liver and drug secretion in the bile, respectively, play a major role in liver drug clearance. Inflammation is well-known to impair expression of these transporters in rodents; data about this topic have been more recently reported in human hepatocytes.
The present review is designed to summarise the effects of pro-inflammatory cytokines such as IL-1beta, TNF-alpha and IL-6 toward human hepatic drug and bile salt transporters.
Recent studies aimed at analyzing transporter expression and activity in cytokines-exposed primary human hepatocytes and well-differentiated human hepatoma cells are resumed and discussed.
RESULTS/CONCLUSION: Exposure to IL-1beta, TNF-alpha or IL-6 markedly alters expression profile of human hepatic transporters. Bile salt transporters as well as sinusoidal solute carrier transporters are usually repressed, whereas ATP-binding cassette drug efflux pumps remain unchanged or are either downregulated or upregulated. These changes are observed at mRNA levels, but also, for some of the transporters, at protein and activity levels. They are likely to contribute to alterations of drug pharmacokinetics, impairment of bile salt secretion and cholestasis caused by inflammation in humans.
参与肝脏药物摄取和胆汁药物分泌的正弦形和胆管状肝药物转运体，在肝脏药物清除中起主要作用。炎症众所周知会损害啮齿动物中这些转运体的表达；最近在人原代肝细胞中也有关于这一主题的数据报道。
本综述旨在总结促炎细胞因子（如 IL-1beta、TNF-alpha 和 IL-6）对人肝药物和胆汁盐转运体的影响。
总结并讨论了近期旨在分析细胞因子暴露的原代人肝细胞和分化良好的人肝癌细胞中转运体表达和活性的研究。
结果/结论：IL-1beta、TNF-alpha 或 IL-6 的暴露显著改变了人肝转运体的表达谱。胆汁盐转运体以及窦状溶质载体转运体通常受到抑制，而 ATP 结合盒药物外排泵保持不变，或者下调或上调。这些变化在 mRNA 水平上观察到，但对于一些转运体，也在蛋白和活性水平上观察到。它们可能导致炎症引起的药物药代动力学改变、胆汁盐分泌受损和胆汁淤积。
