Uridine-5'-triphosphate protects against hepatic- ischemic/reperfusion injury in mice.
OBJECTIVE
Mitochondrial calcium overload triggers apoptosis and also regulates ATP production. ATP and uridine-5'-triphosphate (UTP) depletion from hepatic tissue after ischemia causes cell death. ATP and UTP binds to cell membranes of the hepatocytes through P2Y receptors. Our aim was to investigate the role of UTP on the hepatic injury induced by ischemia.


METHODS
Isolated mouse livers were randomly divided into five groups: (1) control group; (2) ischemic group (90 min); (3) as group 2, but with the administration of UTP; (4) as group 2, but with the administration of suramin, a P2Y antagonist; and (5) as group 3, but with the simultaneous administration of suramin and UTP.


RESULTS
There was a postischemic significant reduction in the release of liver enzymes in the animals pretreated with UTP, the intrahepatic caspase-3 activity was significantly decreased, and the intrahepatic ATP content increased compared with group 2 (ischemic untreated). UTP prevented intracellular Ca overload after hypoxia in hepatocyte cultures. In the UTP-treated groups, significantly fewer apoptotic hepatocyte cells were noted by weaker activation of caspase-3 and by the transferase-mediated dUTP nick end labeling assay. The administration of suramin prevented the beneficial effect of endogenous ATP. UTP treatment attenuated the degradation of IkappaBalpha (nuclear factor-kappaB inhibitor) by 80% during reperfusion with no effect on c-Jun N terminal kinase phosphorylation.


CONCLUSIONS
The administration of UTP before induction of ischemia-reperfusion can attenuate hepatic injury. UTP administration decreased cytosolic Ca overload in hypoxic conditions. UTP-mediated protective effects may be regulated through nuclear factor- kappaB inactivation. These findings have important implications for the potential use of UTP in ischemic hepatic injury.
Ben-Ari
Ziv
Z
Liver Institute, Rabin Medical Center, Beilinson Hospital, Petah Tiqwa, Israel. zbenari@clalit.org.il
Pappo
Orit
O
Yitzhaki
Smadar
S
Cheporko
Yelena
Y
Shainberg
Asher
A
Zinman
Tova
T
Ravid
Amiram
A
Zemel
Romi
R
Bachmatov
Larisa
L
Kurtzwald
Efrat
E
Mor
Eytan
E
Hochhauser
Edith
E
D000410:Alanine Transaminase / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001219:Aspartate Aminotransferases / Q000378:metabolism; D001794:Blood Pressure; D053148:Caspase 3 / Q000378:metabolism; D015687:Cell Hypoxia; D002478:Cells, Cultured; D022781:Hepatocytes / Q000187:drug effects / Q000502:physiology; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000201:enzymology / Q000293:injuries*; D008297:Male; D051379:Mice; D015427:Reperfusion Injury / Q000517:prevention & control*; D013498:Suramin / Q000627:therapeutic use; D014544:Uridine Triphosphate / Q000627:therapeutic use*; D014682:Vena Cava, Inferior / Q000502:physiology
D013498:Suramin; D007770:L-Lactate Dehydrogenase; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D053148:Caspase 3; D014544:Uridine Triphosphate