title: Bezafibrate induces multidrug-resistance P-Glycoprotein 3 expression in cultured human hepatocytes and humanized livers of chimeric mice.
abstract: OBJECTIVE
  A decreased function of multidrug-resistance 3 P-glycoprotein (MDR3), limiting the rate of biliary phospholipid secretion, predisposes individuals to cholestasis and/or cholangitis. Fibrates induce the expression of mdr2 (homolog of human MDR3) in rodents. To investigate the effects of bezafibrate (BF) on the expression levels of MDR3 in cultured human hepatocytes and human livers, the amount of protein and subcellular localization of MDR3 was assessed in HepG2 cells treated with BF and humanized livers of BF-treated chimeric mice.
  
  
  RESULTS
  In HepG2 cells, while treatment with BF did not increase the protein levels of MDR3, the treatment caused a redistribution of MDR3 in the bile canaliculi. In humanized livers of chimeric mice, oral administration of BF induced a large increase in the protein amount of MDR3 and its redistribution in the bile canaliculi. Moreover, the modulatory effects of BF on key factors involved in hepatic cholesterol and bile acid metabolism in human subjects were traced in the humanized livers of BF-treated chimeric mice.
  
  
  CONCLUSIONS
  BF causes an induction of MDR3 expression in human livers. This provides a rationale for the beneficial role of BF in improving cholestasis and/or cholangitis associated with defective MDR3 expression and function in various types of cholestatic hepatobiliary diseases.
authors.affiliation: Department of Gastroenterology, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Ibaraki, Japan.
authors.forename: Junichi
authors.initials: J
authors.lastname: Shoda
authors.forename: Kosuke
authors.initials: K
authors.lastname: Okada
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Inada
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kusama
authors.forename: Hirotoshi
authors.initials: H
authors.lastname: Utsunomiya
authors.forename: Koji
authors.initials: K
authors.lastname: Oda
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Yokoi
authors.forename: Katsutoshi
authors.initials: K
authors.lastname: Yoshizato
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Suzuki