Assessment of ileal epithelial P-glycoprotein dysfunction induced by ischemia/reperfusion using in vivo animal model.
We presented the ischemia/reperfusion (I/R) model which can evaluate changes in P-glycoprotein (P-gp) function induced by lipid peroxidation using surgical-sutures connected with the spring balance. The superior mesenteric artery and vein was occluded by hanging itself using surgical-sutures connected with the spring balance for 60 min (ischemia), followed by reperfusion by cutting of sutures. To determine the hanging force of blood vessel during ischemia, treatment at the hanging force of 50g load, 100g load and 150g load for 60 min was carried out and survival rate was evaluated. Although our 150g load group had some effect on survival, the survival was 100% in the case of 50g and 100g load groups. Thiobarbituric acid-reactive substance (TBA-RS) as an indicator of lipid peroxidation and P-gp expression level after I/R was increased and decreased in a load-dependent manner during ischemia, respectively. Also, the decrease in the level of mdr1a mRNA and function of P-gp by I/R depended on load during ischemia. The changes in TBA-RS, P-gp expression level and P-gp function observed in this study corresponded with our in vitro I/R model reported previously. In conclusion, it was shown that this in vivo I/R model can evaluate the function of P-gp through lipid peroxidation.
Tomita
Mikio
M
Department of Drug Absorption and Pharmacokinetics, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan. tomita@ps.toyaku.ac.jp
Takizawa
Yusuke
Y
Kishimoto
Hisanao
H
Hayashi
Masahiro
M
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000502:physiology*; D000818:Animals; D057167:Claudins; D007082:Ileum / Q000098:blood supply*; D007413:Intestinal Mucosa / Q000503:physiopathology*; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D017538:Mesenteric Artery, Superior / Q000502:physiology; D008642:Mesenteric Veins / Q000502:physiology; D023421:Models, Animal; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000503:physiopathology*; D020112:Rhodamine 123 / Q000378:metabolism; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism; D000097202:ATP-Binding Cassette Sub-Family B Member 4
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D057167:Claudins; D008565:Membrane Proteins; D012333:RNA, Messenger; D020112:Rhodamine 123; D017392:Thiobarbituric Acid Reactive Substances; D000097202:ATP-Binding Cassette Sub-Family B Member 4; C524370:Cldn7 protein, rat; C095122:multidrug resistance protein 3