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.