Multidrug resistance3 is in situ detected in the liver of patients with primary biliary cirrhosis, and induced in human hepatoma cells by bezafibrate.
Bezafibrate has been empirically used for the treatment of primary biliary cirrhosis. Although its clinical efficacy has been demonstrated, the therapeutic mechanism of action of this drug remains unclear. We suggested that multi-drug resistance (MDR) 3 plays an important role as a mediator of bezafibrate. We adopted a human hepatoma cell line to elucidate the up-regulating effect of bezafibrate. To analyze the effects on mRNA, the dose effect was assessed by slot-blot study, the time course by real time PCR, and the subcellular location was determined by in situ hybridization. The results revealed that MDR3 mRNA reached a peak level 12h after the administration of bezafibrate, and dose dependency was observed. We also investigated the interaction of bile acid and bezafibrate. A low dose of chenodeoxycholic acid could become a co-effecter of bezafibrate. In the protein analysis, a precursor protein was induced by bezafibrate. Even in the cell line endogenously expressing MDR3, the expression of the protein was found to be modulated. We identified MDR3 mRNA in the livers of PBC patients using a sensitive in situ hybridization study. The present findings indicate that PBC patients can respond to bezafibrate, and therefore receive clinical benefits from this medication.
Matsumoto
Takayuki
T
Third Department of Internal Medicine, Kansai Medical University, 10-15 Fumizonocho, Moriguchi, Osaka 570-8506, Japan.
Miyazaki
Hiroaki
H
Nakahashi
Yoshitsugu
Y
Hirohara
Junko
J
Seki
Toshihito
T
Inoue
Kyoichi
K
Okazaki
Kazuichi
K