CARBON TETRACHLORIDE-INDUCED HEPATIC-INJURY IS ASSOCIATED WITH GLOBALDNA HYPOMETHYLATION AND HOMOCYSTEINEMIA - EFFECT OF S-ADENOSYLMETHIONINE TREATMENT

Carbon tetrachloride (CCl4) administration to rats produces hepatic ci rrhosis and supplementation with S-adenosylmethionine (SAM) can partia lly prevent CCl4-induced liver injury. These effects are thought to be caused by oxidative stress and the subsequent formation of free radic als, but the mechanism whereby this occurs and the accurate nature of the mechanisms by which SAIM exerts its protective action are not well understood. The effect of short-term administration of CCl4 on hepati c DNA methylation and on SAM and S-adenosylhomocysteine (SAH) were ass essed. CCl4 administration to rats for 3 weeks resulted in hypomethyla tion of liver DNA, determined by comparing the extent to which DNA fro m livers of control or treated animals could be methylated in vitro us ing [H-3-methyl] SAM as methyl donor. This CCl4 effect on DNA methylat ion was corrected by the administration of SAM (10 mg/kg/d, intramuscu larly), with values of methyl groups incorporation comparable with tho se observed in the control animals. Hepatic SAM was decreased by CCl4 (65.3 +/- 5.27 vs, 102.2 a 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 c ontrol rats to 0.94 in CCl4-treated animals (P <.05), SAM treatment pa rtially prevented (P <.05) the reduction of the ratio SAM/SAH induced by CCl4. CCl4 also induced a marked elevation of serum homocysteine le vels (more than 20-fold; P <.001), which was partially prevented by SA M administration, A decrease in serum methionine concentration was als o observed (20.87 +/- 1.76 vs, 31.25 +/- 2.37 mu mol/L; P <.05) in res ponse to CCl4, whereas cystathionine levels remained unchanged. Hepati c folate was reduced by CCl4 (11.2 +/- 2.1 vs. 17.6 +/- 1.8 mu g/g; P <.05) and SAM treatment prevented this effect (P <.05). Hepatic glutat hione (reduced form) and the activity of the enzyme SAM synthetase, wh ich have been found to be reduced after the administration of CCl4 to rats for longer periods, were unchanged after treatment with the hepat otoxic agent for only 3 weeks. It is proposed that CCl4 disrupts the d istribution of homocysteine between remethylation and its degradation via the transsulphuration pathway and that SAM, by resetting the methy lation ratio, restores this equilibrium.