THE EFFECT OF ETHANOL ON ONE-CARBON METABOLISM - INCREASED METHIONINECATABOLISM AND LIPOTROPE METHYL-GROUP WASTAGE

Deficiency of choline and methionine produces hepatic steatosis simila r to that seen with ethanol, and supplementation with these lipotropes can prevent ethanol-induced fatty liver. These effects are thought to occur through alterations in membrane phospholipid metabolism, but th e mechanism whereby this occurs and the precise nature of the changes brought about by ethanol in the interactions of choline and methionine metabolism remain unclear. Through the known effects on hepatic gluta thione (which requires as a precursor a product of methionine cataboli sm), ethanol might affect hepatic one-carbon metabolism, which require s the participation of both methionine and choline in the transfer of methyl groups. This has been investigated with a radiorespirometric te chnique to assess the in vivo oxidation of the methyl groups of lipotr opes and their intermediates in ethanol- and control-fed rats. Enzyme activities of one-carbon transfer reactions and the hepatic levels of methionine and alpha-aminobutyrate, an end product of methionine catab olism, have been measured. The effect of ethanol feeding on hepatic S- adenosylmethionine and S-adenosylhomocysteine has also been assessed. Ethanol increases the oxidation to carbon dioxide of the methyl group of methionine by a factor of 2.9 (p = 0.002) and produces a 3.6-fold ( p = 0.000 1) accumulation of alpha-aminobutyrate, indicating a marked increase in methionine catabolism. Hepatic methionine levels are uncha nged by ethanol, however, and this may be explained by a dramatic incr ease in the turnover of the methyl groups of choline and betaine in re sponse to ethanol (times 3.6 and 4.2, respectively, p < 0.003), sugges ting greatly increased use of the choline oxidation pathway to remethy late homocysteine through betaine homocysteine methyltransferase. The activity of this enzyme is more than doubled (p = 0.002) in ethanol-fe d animals, and that of methionine synthase is significantly decreased. Hepatic S-adenosylmethionine is decreased by ethanol (59.6 vs. 100.9 nmol/gm, p < 0.001), possibly representing increased consumption, and S-adenosylhomocysteine is increased. We propose that ethanol stimulate s catabolism of methionine to generate cysteine and replenish glutathi one, but at the same time, the cell attempts to conserve methionine th rough a futile cycle of enhanced choline oxidation. The result is a dr amatic wastage of methyl groups.