Evaluation of the potential protective effect of 21-aminosteroid U-74389G on liver injury induced by reduced and prolonged partial hepatic ischaemia reperfusion in rats.
The protective effect of the 21-aminosteroid U-74389G was studied in an experimental model of partial ischaemia reperfusion liver injury. Previous studies have proven the remarkable potency of 21-aminosteroids to prevent oxidant-induced cell injury in vitro and in vivo. However, the capability of these compounds to limit oxidative injury in clinical trials has been considered to be less certain. The potential protective effect exerted by U-74389G on reduced and prolonged models of ischaemia reperfusion liver injury was studied in male rats subjected to 75 min. of segmentary hepatic ischaemia followed by 1 or 24 hr of reperfusion. Liver injury was evaluated by measuring serum levels of liver enzymes and by histopathological studies. The oxidative status of liver cells was measured by evaluating the levels of liver lipid peroxidation products such as malondialdehyde and the levels of reduced glutathione. Our results lead us to think that treatment with U-74389G (6 mg/kg) does not bring about any protective effect neither in the levels of transaminases nor in the percentage of hepatocellular necrosis and cellular infiltration observed in any reperfusion-period groups. In fact and in contrast with our expectations, U-74389G seemed to increase enzyme release. Furthermore, at the dose used, this 21-aminosteroid is not capable of inhibiting the lipoperoxidation processes, although it induced an important increase of GSH levels at any time-period of reperfusion. This last finding seem to suggest that U-74389G could increase the resistance to oxidant-induced liver tissue damage. However, our results show that, at the dose used, this compound did not exert any protective effect on liver tissue, thus explaining, at least partially, the absence of beneficial effects on the part of these compounds in clinical trials carried out to limit organ injury in transplants.
Zumbado
Manuel
M
Toxicology Unit, Department of Clinical Sciences, Health Sciences Center, University of Las Palmas de Gran Canaria, 35080-Las Palmas de Gran Canaria, Spain.
Domínguez-Díez
Agustín
A
Hernández
Juan Ramón
JR
Díaz
José María
JM
Palomar
Rosa
R
García-Plaza
Guillermo
G
Navarro
Domingo
D
Boada
Luis D
LD
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D004195:Disease Models, Animal; D007511:Ischemia / Q000150:complications*; D008099:Liver / Q000098:blood supply*; D008297:Male; D011281:Pregnatrienes / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000209:etiology / Q000517:prevention & control*
D000975:Antioxidants; D011281:Pregnatrienes; C074965:U 74389F