Balance between oxidative damage and proliferative potential in an experimental rat model of CCl4-induced cirrhosis: protective role of adenosine administration.
Oxidative stress and its consequent lipid peroxidation (LP) exert harmful effects, which have been currently involved in the generation of carbon tetrachloride-induced cirrhosis. However, the recent report that "physiological" LP can be associated with liver regeneration (LR) makes it necessary to discriminate between oxidative stress-induced and LR-associated LP. In rats rendered cirrhotic by continuous CCl4 administration for 4 weeks, moderate cell necrosis and fine fatty infiltration were found. The histological abnormalities were accompanied by increased LP, mainly accounted for by the microsomal and cytosolic fractions and evidence of oxidative stress (decreased hepatic glutathione content and changes in xanthine oxidase and pentose phosphate pathway activities). After 8 weeks, a micronodular cirrhosis developed, but oxidative stress was greatly attenuated, only persisting in the enhanced LP confined to microsomes. Simultaneous administration of adenosine, a reliable hepatoprotector that readily prevents the onset of liver fibrosis, was able to block the oxidative stress induced by the long-term CCl4 treatment but elicited a selective subcellular distribution of increased LP, similar to that found during LR. The adenosine-induced changes in liver LP (mainly in the nuclear fraction) correlated with an increased activity of thymidine kinase. Therefore, data suggest that adenosine-mediated preservation of energy availability and mitochondrial function could participate in preventing the onset of oxidative stress in cirrhotic rats. The latter could induce a successful liver recovery, curtailing the sequence of events leading to fibrogenesis.
Hernández-Muñoz
R
R
Departamento de Bioenergética, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, Ciudad de México, D.F.
Díaz-Muñoz
M
M
López
V
V
López-Barrera
F
F
Yáñez
L
L
Vidrio
S
S
Aranda-Fraustro
A
A
Chagoya de Sánchez
V
V
D000241:Adenosine / Q000494:pharmacology*; D000466:Alkadienes / Q000378:metabolism; D000818:Animals; D002251:Carbon Tetrachloride; D002455:Cell Division; D004247:DNA / Q000096:biosynthesis; D004798:Enzymes / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008106:Liver Cirrhosis, Experimental / Q000139:chemically induced / Q000473:pathology*; D008163:Luminescent Measurements; D008297:Male; D010084:Oxidation-Reduction; D051381:Rats; D017208:Rats, Wistar; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism
D000466:Alkadienes; D004798:Enzymes; D017392:Thiobarbituric Acid Reactive Substances; D004247:DNA; D002251:Carbon Tetrachloride; D005978:Glutathione; D000241:Adenosine