Betaine Lowers Elevated S-Adenosylhomocysteine Levels in Hepatocytes from Ethanol-Fed Rats

Abstract

Previous studies showed that chronic ethanol administration inhibits methionine synthase activity, resulting in impaired homocysteine remethylation to form methionine. This defect in homocysteine remethylation was shown to increase plasma homocysteine and to interfere with the production of hepatic S-adenosylmethionine (SAM) in ethanol-fed rats. These changes were shown to be reversed by the administration of betaine, an alternative methylating agent. This study was undertaken to determine additional effects of ethanol on methionine metabolism and their functional consequences. The influences of methionine loading and betaine supplementation were also evaluated. Adult Wistar rats were fed ethanol or a control Lieber-DeCarli liquid diet for 4 wk, and metabolites of the methionine cycle were measured in vitro in isolated hepatocytes under basal and methionine-supplemented conditions. S-Adenosylhomocysteine (SAH) concentrations were elevated in hepatocytes isolated from ethanol-fed rats compared with controls and in hepatocytes from both groups when supplemented with methionine. The addition of betaine to the methionine-supplemented incubation media reduced the elevated SAH levels. The decrease in the intracellular SAH:SAM ratio due to ethanol consumption inhibited the activity of the liver-specific SAM-dependent methyltransferase, phosphatidylethanolamine methyltransferase. Our data indicate that betaine, by remethylating homocysteine and removing SAH, overcomes the detrimental effects of ethanol consumption on methionine metabolism and may be effective in correcting methylation defects and treating liver diseases.

Role of elevated S-adenosylhomocysteine in rat hepatocyte apoptosis: Protection by betaine

“…Hepatocytes were obtained from the livers of the rats by a modified collagenase-perfusion technique as previously described [22]. Viabilities of the different cell populations were determined by trypan blue exclusion, and only cell preparations attaining a viability of >90% were used.…”

“…SAH levels: Hepatocyte pellets were homogenized in 0.5 mol/L HClO 4 , and the filtered acid extracts directly subjected to HPLC analysis for the determination of hepatocellular SAH levels following the procedure of Fu et al [38] as detailed in our publication [22].…”

“…This defect ultimately results in an increased generation of the potentially toxic agent, homocysteine, which is released from the liver [12][13][14][19][20][21]. Ethanol consumption also results in increased hepatocellular levels of S-adenosylhomocysteine (SAH) [3,21,22]-a product of methyl transfer reactions involving S-adenosylmethionine (SAM) and the metabolic precursor of homocysteine and adenosine. Since the reaction that converts SAH to homocysteine and adenosine (catalyzed by SAH hydrolase) is reversible and proceeds toward hydrolysis only if the products are removed [15], the accumulation of homocysteine follow- ing ethanol exposure drives SAH hydrolase to catalyze the energetically favorable reverse reaction resulting in increased SAH generation [22].…”

“…As an osmolyte, betaine protects cells, proteins and enzymes from environmental stress, including extreme temperature, high salinity and low water content. As a methyl donor, betaine participates in the methionine cycle, and by remethylating homocysteine via betaine-homocysteine-methyltransferase (BHMT) has been shown to alleviate ethanol-induced changes in intracellular SAH levels [22].…”

Herbal and polymeric approaches for liver-targeting drug delivery: novel strategies and their significance

“…It shows that betaine has protective effect against ethanol induced vitamin A depletion. It also protects from peroxidative injury in experimental models affected from liver disorders (Barak et al, 2003;Kanbak et al, 2009;Kharbanda, 2009). Smoking is also a major factor in hepatotoxicity (Lee, 2003).…”