Fiche publication
Date publication
avril 2013
Auteurs
Membres identifiés du Cancéropôle Est :
Dr MULLER Christian
,
Pr UBEAUD-SEQUIER Genevieve
Tous les auteurs :
Saab L, Peluso J, Muller CD, Ubeaud-Sequier G
Lien Pubmed
Résumé
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-alpha + 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.
Référence
Cytometry A. 2013 Apr;83(4):403-8
