Rapamycin induces heme oxygenase-1 in liver but inhibits bile flow recovery after ischemia.
OBJECTIVE
Rapamycin, which is employed in the management of patients undergoing liver surgery, induces the synthesis of heme oxygenase-1 (HO-1) in some non-liver cell types. The aim was to investigate whether rapamycin can induce HO-1 expression in the liver, and to test the effects of rapamycin on liver function in the early phase of ischemia reperfusion (IR) injury.


METHODS
Isolated rat hepatocytes and a rat model of segmental hepatic ischemia and reperfusion were employed. Bile flow was measured gravimetrically or by using indocyanine green. mRNA and protein (by quantitative PCR and Western blot, respectively) and blood concentrations of rapamycin, bilirubin, and liver marker enzymes were measured.


RESULTS
In isolated hepatocytes, rapamycin induced a 6-fold increase in HO-1, comparable to that induced by cobalt proporphyrin (CoPP), and a 2-fold increase in peroxiredoxin-1. Pretreatment of rats with rapamycin resulted in a small increase in liver HO-1 expression, a 20% inhibition of the basal rate of bile flow, and a 50% inhibition in the rate of bile flow recovery after ischemia. CoPP increased basal bile flow by 20% and inhibited bile flow recovery by 50%. These effects were associated with small increases in the blood concentrations of bilirubin and liver marker enzymes.


CONCLUSIONS
Rapamycin, through HO-1 induction, has the potential to protect the liver against damage in the late phase of IR. The inhibition by rapamycin of bile flow indicates that its actions on liver function in the acute phase of IR injury are complex.
Department of Medical Biochemistry, Flinders Medical Centre and School of Medicine, Flinders University, Adelaide, South Australia, Australia. Greg.Barritt@flinders.edu.au
Alwine
A
Kist
Joris
J
Wakkie
Max
M
Madu
Ruth
R
Versteeg
Judith
J
ten Berge
Andrej
A
Nikolic
Vincent B
VB
Nieuwenhuijs
Robert J
RJ
Porte
Robert T A
RT
Padbury
Greg J
GJ
Barritt
D000818:Animals; D000900:Anti-Bacterial Agents / Q000097:blood / Q000494:pharmacology; D001646:Bile / Q000378:metabolism*; D001663:Bilirubin / Q000097:blood; D004195:Disease Models, Animal; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D051547:Heme Oxygenase-1 / Q000235:genetics* / Q000378:metabolism; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D016031:Liver Transplantation; D008297:Male; D061251:Primary Cell Culture; D011524:Protoporphyrins / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology*; D020123:Sirolimus / Q000097:blood / Q000494:pharmacology*
D000900:Anti-Bacterial Agents; D011524:Protoporphyrins; C007095:cobaltiprotoporphyrin; D051547:Heme Oxygenase-1; D001663:Bilirubin; D020123:Sirolimus