FEEDING S-ADENOSYL-L-METHIONINE ATTENUATES BOTH ETHANOL-INDUCED DEPLETION OF MITOCHONDRIAL GLUTATHIONE AND MITOCHONDRIAL DYSFUNCTION IN PERIPORTAL AND PERIVENOUS RAT HEPATOCYTES

Mitochondrial glutathione plays an important role in maintaining a fun ctionally competent organelle. Previous studies have shown that ethano l feeding selectively depletes the mitochondrial glutathione pool, mor e predominantly in mitochondria from perivenous hepatocytes. Because S -adenosyl-L-methionine (SAM) is a glutathione precursor and maintains the structure and function of biological membranes, the purpose of the present study was to determine the effects of SAM on glutathione and function of perivenous (PV) and periportal (PP) mitochondria from chro nic ethanol-fed rats. SAM administration resulted in a significant inc rease in the basal cytosol and mitochondrial glutathione in both PP an d PV cells from both pair-fed or ethanol-fed groups. When hepatocytes from ethanol-fed rats supplemented with SAM were incubated with methio nine plus serine or N-acetylcysteine, mitochondrial glutathione increa sed in parallel with cytosol, an effect not observed in cells from eth anol-fed rats without SAM. Feeding equimolar N-acetylcysteine raised c ytosol glutathione but did not prevent the mitochondrial glutathione d efect. In addition, SAM feeding resulted in significant preservation o f cellular adenosine triphosphate (ATP) levels (23% to 43%), mitochond rial membrane potential (17% to 25%), and the uncoupler control ratio (UCR) of respiration (from 5.1 +/- 0.7 to 7.3 +/- 0.6 and 2.1 +/- 0.3 to 6.1 +/- 0.7) for PP and PV mitochondria, respectively. Thus, these effects of SAM suggest that it may be a useful agent to preserve the d isturbed mitochondrial integrity in liver disease caused by alcoholism through maintenance of mitochondrial glutathione transport.