Cyclosporine a augments P-glycoprotein expression in the regenerating rat liver.
In the liver, the multidrug resistance (MDR) protein P-glycoprotein (P-gp) is physiologically expressed at the bile canalicular membrane, where it participates in the biliary excretion of various lipophilic drugs and xenobiotics. Previous studies showed that the immunosuppressive agent cyclosporine A (CsA) modulates P-gp and exerts a hepatotrophic influence in the regenerating liver. Hepatocytes isolated from regenerating rat liver, after 2/3 partial hepatectomy (PH 2/3), were used as an in vivo experimental model of cells with high proliferating activity in order to investigate whether CsA influences cellular levels of P-gp in those cells. Male Wistar rats were treated with CsA (20 mg/kg body weight) for 4 d preoperatively and 1 d postoperatively, and regenerating hepatocytes were isolated by collagenase perfusion 12, 24 and 48 h after PH 2/3. Flow cytometry and Western blotting studies with the monoclonal antibodies C494 and C219 showed that after PH 2/3, cellular levels of P-gp were initially suppressed, 12 h after PH 2/3, by 23%, but were significantly elevated thereafter, 24 and 48 h after PH 2/3 by 28% and 73%, respectively. In CsA pretreated animals, P-gp levels were increased even in normal hepatocytes by 34%, and an additional augmentation was seen in hepatocytes from 24 and 48 h regenerating livers (60% and 56%, respectively). In summary, we demonstrate for the first time that CsA has an additive effect on the expression of P-glycoprotein during liver regeneration in the rat. Therefore, induction of P-gp might also be considered in patients receiving CsA after liver transplantation for hepatocellular carcinoma and chemotherapy as an adjuvant treatment for the prevention of tumor recurrence.
Daoudaki
Maria
M
Department of Biological Chemistry, Aristotelian University of Thessaloniki Medical School, Greece. daoudaki@med.auth.gr
Fouzas
Ioannis
I
Stapf
Verena
V
Ekmekcioglu
Cem
C
Imvrios
George
G
Andoniadis
Antonios
A
Demetriadou
Aphrodite
A
Thalhammer
Theresia
T
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000276:immunology / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western / Q000379:methods; D016572:Cyclosporine / Q000097:blood / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005434:Flow Cytometry / Q000295:instrumentation / Q000379:methods; D015870:Gene Expression / Q000187:drug effects*; D006498:Hepatectomy / Q000379:methods; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D008115:Liver Regeneration / Q000187:drug effects* / Q000502:physiology; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D004791:Enzyme Inhibitors; D016572:Cyclosporine