RT Journal Article
SR Electronic
T1 Itraconazole-Induced Cholestasis: Involvement of the Inhibition of Bile Canalicular Phospholipid Translocator MDR3/ABCB4
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 241
OP 250
DO 10.1124/mol.110.067256
VO 79
IS 2
A1 Takashi Yoshikado
A1 Tappei Takada
A1 Takehito Yamamoto
A1 Hiroko Yamaji
A1 Kousei Ito
A1 Tomofumi Santa
A1 Hiromitsu Yokota
A1 Yutaka Yatomi
A1 Haruhiko Yoshida
A1 Jun Goto
A1 Shoji Tsuji
A1 Hiroshi Suzuki
YR 2011
UL http://molpharm.aspetjournals.org/content/79/2/241.abstract
AB Biliary secretion of bile acids and phospholipids, both of which are essential components of biliary micelles, are mediated by the bile salt export pump (BSEP/ABCB11) and multidrug resistance 3 P-glycoprotein (MDR3/ABCB4), respectively, and their genetic dysfunction leads to the acquisition of severe cholestatic diseases. In the present study, we found two patients with itraconazole (ITZ)-induced cholestatic liver injury with markedly high serum ITZ concentrations. To characterize the effect of ITZ on bile formation in vivo, biliary bile acids and phospholipids were analyzed in ITZ-treated rats, and it was revealed that biliary phospholipids, rather than bile acids, were drastically reduced in the presence of clinically relevant concentrations of ITZ. Moreover, by using MDR3-expressing LLC-PK1 cells, we found that MDR3-mediated efflux of [14C]phosphatidylcholine was significantly reduced by ITZ. In contrast, BSEP-mediated transport of [3H]taurocholate was not significantly affected by ITZ, which is consistent with our in vivo observations. In conclusion, this study suggests the involvement of the inhibition of MDR3-mediated biliary phospholipids secretion in ITZ-induced cholestasis. Our approach may be useful for analyzing mechanisms of drug-induced cholestasis and evaluating the cholestatic potential of clinically used drugs and drug candidates.