Olivier Fardel1, Marc Le Vée. 1. EA 4427 SeRAIC, Faculté de Pharmacie, Rennes, France. olivier.fardel@univ-rennes1.fr
Abstract
BACKGROUND: 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. OBJECTIVE: 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. METHODS: 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.
BACKGROUND: 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. OBJECTIVE: 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. METHODS: Recent studies aimed at analyzing transporter expression and activity in cytokines-exposed primary human hepatocytes and well-differentiated humanhepatoma 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.
Authors: Raymond Evers; Micheline Piquette-Miller; Joseph W Polli; Frans G M Russel; Jason A Sprowl; Kimio Tohyama; Joseph A Ware; Saskia N de Wildt; Wen Xie; Kim L R Brouwer Journal: Clin Pharmacol Ther Date: 2018-07-12 Impact factor: 6.875