Itraconazole-induced cholestasis: involvement of the inhibition of bile canalicular phospholipid translocator MDR3/ABCB4.
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.
Department of Pharmacy, University of Tokyo Hospital, Faculty of Medicine, the University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
Takashi
T
Yoshikado
Tappei
T
Takada
Takehito
T
Yamamoto
Hiroko
H
Yamaji
Kousei
K
Ito
Tomofumi
T
Santa
Hiromitsu
H
Yokota
Yutaka
Y
Yatomi
Haruhiko
H
Yoshida
Jun
J
Goto
Shoji
S
Tsuji
Hiroshi
H
Suzuki
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D000935:Antifungal Agents / Q000097:blood / Q000633:toxicity*; D001648:Bile Canaliculi / Q000187:drug effects* / Q000378:metabolism; D015153:Blotting, Western; D002779:Cholestasis / Q000139:chemically induced*; D017964:Itraconazole / Q000097:blood / Q000633:toxicity*; D018374:LLC-PK1 Cells; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley
D018435:ATP Binding Cassette Transporter, Subfamily B; D000935:Antifungal Agents; D017964:Itraconazole; C095122:multidrug resistance protein 3