title: Implication of hepatic transporters (MDR1 and MRP2) in inflammation-associated idiosyncratic drug-induced hepatotoxicity investigated by microvolume cytometry.
abstract: Idiosyncratic drug-induced hepatotoxicity accounts for about 13% of all cases of acute liver failure, therefore cited as the most frequent reason for post-marketing drug withdrawal. Despite this, the underlying mechanisms remain poorly understood due to lack in adequate screening assays and predictive in vitro models. Hepatic transporters play a crucial role in the absorption, distribution, and elimination of both endogenous substrates and xenobiotics. Defects in transporter function can lead to altered drug disposition, including toxicity and loss of efficacy. Inflammation is one condition for demonstrated variable drug response, attributed in part, to changes in function of drug transporters. The present study investigates the implication of two important hepatic transporters (MDR1 and MRP2) in idiosyncratic drug-induced hepatotoxicity in the presence and absence of an inflammatory context. The synergistic effect of idiosyncratic drugs (Trovafloxacin, nimesulide, telithromycin, and nefazodone) and inflammatory stimuli (TNF-α + LPS) on the efflux activity of hepatic transporters was studied using microvolume cytometry. Our results demonstrated on the one hand that both MDR1 and MRP2 are variably implicated in idiosyncratic drug-induced liver injury and on the other hand that the occurrence of an inflammatory reaction during idiosyncratic drug therapy can noticeably modulate this implication. In the absence of an inflammatory stress, none of the four tested drugs modulated the efflux activity of MRP2; nevertheless telithromycin and nefazodone inhibited the efflux activity of MDR1. Upon occurrence of an inflammatory stress, the inhibitory potential of trovafloxacin, nimesulide, and nefazodone on the efflux activity of MRP2 was noticeably revealed, while the telithromycin and nefazodone-induced inhibition of MDR1 was clearly attenuated. Knowledge of underlying mechanisms may significantly contribute to elimination of potential hepatotoxic drugs long before marketing and to prevention of drug-induced hepatotoxicity.
authors: UMR CNRS 7200, Laboratoire d'Innovation Thérapeutique, Université de Strasbourg, FMTS, Faculté de Pharmacie, Illkirch, France.
authors: Lea
authors: L
authors: Saab
authors: Jean
authors: J
authors: Peluso
authors: Christian D
authors: CD
authors: Muller
authors: Genevieve
authors: G
authors: Ubeaud-Sequier
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics* / Q000378:metabolism; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics* / Q000378:metabolism; D001692:Biological Transport / Q000187:drug effects; D056486:Chemical and Drug Induced Liver Injury / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D005434:Flow Cytometry / Q000379:methods; D024841:Fluoroquinolones / Q000633:toxicity; D005786:Gene Expression Regulation / Q000187:drug effects; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D048628:Ketolides / Q000633:toxicity; D008070:Lipopolysaccharides / Q000494:pharmacology; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009287:Naphthyridines / Q000633:toxicity; D010879:Piperazines; D013449:Sulfonamides / Q000633:toxicity; D014230:Triazoles / Q000633:toxicity; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D015262:Xenobiotics / Q000633:toxicity*; D000097202:ATP-Binding Cassette Sub-Family B Member 4
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D024841:Fluoroquinolones; D048628:Ketolides; D008070:Lipopolysaccharides; D009287:Naphthyridines; D010879:Piperazines; D013449:Sulfonamides; D014230:Triazoles; D014409:Tumor Necrosis Factor-alpha; D015262:Xenobiotics; D000097202:ATP-Binding Cassette Sub-Family B Member 4; C513055:ABCB1 protein, human; C051752:nefazodone; C080163:trovafloxacin; C106791:telithromycin; C012655:nimesulide