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Carbon tetrachloride–induced hepatic injury is associated with global DNA hypomethylation and homocysteinemia: Effect of S ‐adenosylmethionine treatment
Author(s) -
VarelaMoreiras Gregorio,
AlonsoAperte Elena,
Rubio Mireia,
Gasso Marta,
Deulofeu Ramón,
Alvarez Luis,
Caballería Juan,
Rodés Juan,
Mato José M.
Publication year - 1995
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.1840220442
Subject(s) - ccl4 , carbon tetrachloride , oxidative stress , medicine , dna methylation , chemistry , liver injury , endocrinology , cirrhosis , methylation , homocysteine , biochemistry , dna , biology , gene expression , gene , organic chemistry
Carbon tetrachloride (CCl 4 ) administration to rats produces hepatic cirrhosis and supplementation with S ‐adenosylmethionine (SAM) can partially prevent CCl 4 ‐induced liver injury. These effects are thought to be caused by oxidative stress and the subsequent formation of free radicals, but the mechanism whereby this occurs and the accurate nature of the mechanisms by which SAM exerts its protective action are not well understood. The effect of short‐term administration of CCl 4 on hepatic DNA methylation and on SAM and S ‐adenosylhomocysteine (SAH) were assessed. CCl 4 administration to rats for 3 weeks resulted in hypomethylation of liver DNA, determined by comparing the extent to which DNA from livers of control or treated animals could be methylated in vitro using [ 3 H‐methyl] SAM as methyl donor. This CCl 4 effect on DNA methylation was corrected by the administration of SAM (10 mg/kg/d, intramuscularly), with values of methyl groups incorporation comparable with those observed in the control animals. Hepatic SAM was decreased by CCl 4 (65.3 ± 5.27 vs. 102.2 ± 4.89 nmol/g; P < .05) and SAH was increased (69.5 ± 14.6 vs. 29.4 ± 3.83 nmol/g; P < .05). This led to a marked reduction of the SAM/SAH ratio (the methylation ratio) from 3.47 in control rats to 0.94 in CCl 4 ‐treated animals ( P < .05). SAM treatment partially prevented ( P < .05) the reduction of the ratio SAM/SAH induced by CCl 4 . CCl 4 also induced a marked elevation of serum homocysteine levels (more than 20‐fold; P < .001), which was partially prevented by SAM administration. A decrease in serum methionine concentration was also observed (20.87 ± 1.76 vs. 31.25 ± 2.37 μmol/L; P < .05) in response to CCl 4 , whereas cystathionine levels remained unchanged. Hepatic folate was reduced by CCl 4 (11.2 ± 2.1 vs. 17.6 ± 1.8 μg/g; P < .05) and SAM treatment prevented this effect ( P < .05). Hepatic glutathione (reduced form) and the activity of the enzyme SAM synthetase, which have been found to be reduced after the administration of CCl 4 to rats for longer periods, were unchanged after treatment with the hepatotoxic agent for only 3 weeks. It is proposed that CCl 4 disrupts the distribution of homocysteine between remethylation and its degradation via the transsulphuration pathway and that SAM, by resetting the methylation ratio, restores this equilibrium. (H EPATOLOGY 1995; 22:1310–1315.).