S –Adenosyl–L–Methionine Attenuates Alcohol–Induced Liver Injury in the Baboon

Abstract

Chronic ethanol consumption by baboons (50% of energy from a liquid diet) for 18 to 36 mo resulted in significant depletion of hepatic S –adenosyl–L–methionine concentration: 74.6 ± 2.4 nmol/gm vs. 108.9 ± 8.2 nmol/gm liver in controls (p < 0.005). The depletion was corrected with S –adenosyl–L–methionine (0.4 mg/kcal) administration (102.1 ± 15.4 nmol/gm after S –adenosyl–L–methionine-ethanol, with 121.4 ± 11.9 nmol/gm in controls). Ethanol also induced a depletion of glutathione (2.63 ± 0.13 μmol/gm after ethanol vs. 4.87 ± 0.36 μmol/gm in controls) that was attenuated by S –adenosyl–L–methionine (3.89 ± 0.51 μmol/gm in S –adenosyl–L–methionine–methanol vs. 5.22 ± 0.53 μmol/gm in S –adenosyl–L–methionine controls). There was a significant correlation between hepatic S –adenosyl–L–methionine and glutathione level (r = 0.497; p < 0.01). After the baboons received ethanol, we observed the expected increase in circulating levels of the mitochondrial enzyme glutamic dehydrogenase: 95.1 ± 21.4 IU/L vs. 13.4 ± 1.8 IU/L; p < 0.001, whereas in a corresponding group of animals given S –adenosyl–L–methionine with ethanol, the values were only 30.3 ± 7.1 IU/L (vs. 9.6 ± 0.7 IU/L in the S –adenosyl–L–methionine controls). This attenuation by S –adenosyl–L–methionine of the ethanol–induced increase in plasma glutamic dehydrogenase (p < 0.005) was associated with a decrease in the number of giant mitochondria (assessed in percutaneous liver biopsy specimens), with a corresponding change in the activity of succinate dehydrogenase, a mitochondrial marker enzyme. Succinate dehydrogenase activity was increased in liver homogenates of animals fed ethanol (81.4 ± 4.0 mU/mg protein vs. 55.4 ± 2.1 mU/mg in controls; p < 0.001), probably reflecting the increased mitochondrial mass. S –adenosyl–L–methionine decreased succinate dehydrogenase levels (66.7 ± 3.6 mU/mg protein in S –adenosyl–L–methionine–ethanol group vs. 45.5 ± 2.2 mU/mg in S –adenosyl–L–methionine controls; p < 0.001). S –adenosyl–L–methionine supplementation also significantly lessened the ethanol–induced increase of plasma AST. Thus long–term ethanol intake is associated with hepatic S –adenosyl–L–methionine depletion, which can be corrected at least in part by S –adenosyl–L–methionine administration, resulting in an attenuation of some alcohol–induced liver injury.