Carbon tetrachloride-induced hepatic injury is associated with global DNA hypomethylation and homocysteinemia: effect of S-adenosylmethionine treatment.
Carbon tetrachloride (CCl4) administration to rats produces hepatic cirrhosis and supplementation with S-adenosylmethionine (SAM) can partially prevent CCl4-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 CCl4 on hepatic DNA methylation and on SAM and S-adenosylhomocysteine (SAH) were assessed. CCl4 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 [3H-methyl] SAM as methyl donor. This CCl4 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 CCl4 (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 CCl4-treated animals (P < .05). SAM treatment partially prevented (P < .05) the reduction of the ratio SAM/SAH induced by CCl4. CCl4 also induced a marked elevation of serum homocysteine levels (more than 20-fold; P < .001), which was partially prevented by SAM administration.(ABSTRACT TRUNCATED AT 250 WORDS)
Varela-Moreiras
G
G
Instituto de Investigaciones Biomédicas, Consejo Superior de Investigaciones Científicas, Madrid, Spain.
Alonso-Aperte
E
E
Rubio
M
M
Gassó
M
M
Deulofeu
R
R
Alvarez
L
L
Caballería
J
J
Rodés
J
J
Mato
J M
JM
D000818:Animals; D002251:Carbon Tetrachloride; D003540:Cystathionine / Q000097:blood; D004247:DNA / Q000378:metabolism*; D005492:Folic Acid / Q000378:metabolism; D006710:Homocysteine / Q000097:blood; D008099:Liver / Q000378:metabolism; D008106:Liver Cirrhosis, Experimental / Q000139:chemically induced* / Q000517:prevention & control*; D008297:Male; D008715:Methionine / Q000097:blood; D008745:Methylation; D051381:Rats; D017208:Rats, Wistar; D012435:S-Adenosylhomocysteine / Q000378:metabolism; D012436:S-Adenosylmethionine / Q000378:metabolism / Q000627:therapeutic use*
D006710:Homocysteine; D003540:Cystathionine; D012436:S-Adenosylmethionine; D004247:DNA; D005492:Folic Acid; D012435:S-Adenosylhomocysteine; D008715:Methionine; D002251:Carbon Tetrachloride