title: Intestinal P-glycoprotein expression is multimodally regulated by intestinal ischemia-reperfusion.
abstract: OBJECTIVE
  Reactive oxygen species (ROS) have multiple physiological effects that are amount-dependent. ROS are one of the causes of intestinal ischemia-reperfusion (I/R) injury. In this study, we investigated whether the amount of ROS and the degree of intestinal I/R injury affect the expression level of P-glycoprotein (P-gp).
  
  
  METHODS
  . We used hydrogen peroxide (H2O2) as ROS in in vitro experiments. Intestinal I/R model rats, which were subjected 15-min ischemia (I/R-15), were used in in vivo experiments.
  
  
  RESULTS
  P-gp expression in Caco-2 cells was increased in response to 1 µM of H2O2 but decreased upon exposure to 10 mM of H2O2. We previously reported that P-gp expression is decreased after intestinal I/R with 30-min ischemia (I/R-30), which time a large amount of ROS is generated. I/R-15 induced slightly less mucosal and oxidative injury than did I/R-30. P-gp expression in the jejunum was increased at 1 h after I/R-15, and ileal paracellular permeability was increased. The blood concentration of tacrolimus, a P-gp substrate, was lower during 0-20 min but was higher during 40-90 min post-administration compared with that in the sham-operated rats. P-gp expression in the ileum was decreased at 6 h after I/R-15, due to abnormal localization of P-gp, resulting in a high blood tacrolimus concentration in rats reperfused for 6 h.
  
  
  CONCLUSIONS
  ROS multimodally regulate P-gp expression depending on its amount. This is important for understanding the pattern of P-gp expression after intestinal I/R.
authors.affiliation: Hokkaido University.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Terada
authors.forename: Jiro
authors.initials: J
authors.lastname: Ogura
authors.forename: Takashi
authors.initials: T
authors.lastname: Tsujimoto
authors.forename: Kaori
authors.initials: K
authors.lastname: Kuwayama
authors.forename: Takahiro
authors.initials: T
authors.lastname: Koizumi
authors.forename: Shunichi
authors.initials: S
authors.lastname: Sasaki
authors.forename: Hajime
authors.initials: H
authors.lastname: Maruyama
authors.forename: Masaki
authors.initials: M
authors.lastname: Kobayashi
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Yamaguchi
authors.forename: Ken
authors.initials: K
authors.lastname: Iseki
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis* / Q000235:genetics; D000818:Animals; D018938:Caco-2 Cells; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007413:Intestinal Mucosa / Q000378:metabolism*; D007422:Intestines / Q000473:pathology*; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D015427:Reperfusion Injury / Q000235:genetics / Q000378:metabolism*; D013329:Structure-Activity Relationship; D016559:Tacrolimus / Q000097:blood
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D017382:Reactive Oxygen Species; D006861:Hydrogen Peroxide; D016559:Tacrolimus