ETHANOL FEEDING OF MICROPIGS ALTERS METHIONINE METABOLISM AND INCREASES HEPATOCELLULAR APOPTOSIS AND PROLIFERATION

Chronic alcoholism is associated with increased cancer risk that may b e related to ethanol-induced alterations in methionine and deoxynucleo tide metabolism. These metabolic relationships were studied in micropi gs fed diets for 12 months that contained 40% ethanol or cornstarch co ntrol with adequate folate, Ethanol feeding altered methionine metabol ism without changing mean terminal liver folate levels. After initial equilibration to diet, ethanol feeding significantly increased monthly serum homocysteine levels while reducing serum methionine levels over the time course of the experiment. After 12 months, hepatic methionin e synthase activity and the ratio of S-adenosylmethionine (SAM) to S-a denosylhomocysteine (SAH) were significantly reduced in ethanol-fed an imals, whereas the ratio of liver deoxyuridine triphosphate (dUTP) to deoxythymidine triphosphate (dTTP) was increased and correlated invers ely with methionine synthase activity, These findings were associated with increased frequency of hepatocytes with apoptotic bodies and posi tivity for pro liferating cell nuclear antigen (PCNA) in livers from e thanol-fed minipigs, These studies suggest that chronic ethanol feedin g perturbs methionine metabolism by impairment of methionine synthase activity, resulting in deoxynucleoside triphosphate (dNTP) imbalance, increased apoptosis, and regenerative proliferation, These biochemical alterations may provide a promoting environment for carcinogenesis du ring long-term ethanol exposure.