Ethanol feeding of micropigs alters methionine metabolism and increases hepatocellular apoptosis and proliferation

Abstract

Chronic alcoholism is associated with increased can-and colonic epithelial cell dysplasia in ulcerative colitis cer risk that may be related to ethanol-induced alter-patients. 3 Pretreatment of folate-deficient rats with diations in methionine and deoxynucleotide metabolism. methylhydrazine resulted in a threefold increase in the These metabolic relationships were studied in micropigs incidence of neoplasia of the colonic epithelium as fed diets for 12 months that contained 40% ethanol or compared with rats fed folate-adequate diets.4 Others cornstarch control with adequate folate. Ethanol feed-demonstrated increased induction of rectal neoplasms ing altered methionine metabolism without changing in dimethylhydrazine-treated rats after ethanol-conmean terminal liver folate levels. After initial equilibrataining diets in association with increased mucosal action to diet, ethanol feeding significantly increased cumulation of acetaldehyde.5 As reviewed, 6 several epimonthly serum homocysteine levels while reducing sedemiological studies found an association of excessive rum methionine levels over the time course of the experiment. After 12 months, hepatic methionine synthase ac-alcohol consumption and increased risk of oropharyntivity and the ratio of S-adenosylmethionine (SAM) to geal, esophageal, and colorectal cancer. Two separate S-adenosylhomocysteine (SAH) were significantly re-large studies linked the relative risk of colorectal canduced in ethanol-fed animals, whereas the ratio of liver cer among consumers of alcohol to dietary folate intake, deoxyuridine triphosphate (dUTP) to deoxythymidine one study showing the greatest risk of rectal cancer triphosphate (dTTP) was increased and correlated in-among men consuming excessive alcohol and low di- The relationship between folate deficiency and alcopairment of methionine synthase activity, resulting in hol intake as cancer risk factors may reflect the biodeoxynucleoside triphosphate (dNTP) imbalance, in-chemical interactions between ethanol, folate, and mecreased apoptosis, and regenerative proliferation. These thionine metabolism.9 In addition to direct oxidative biochemical alterations may provide a promoting envi-destruction of the folic acid molecule by acetaldehyde, ethanol feeding of rats caused significant reduction of Both folate deficiency and chronic alcoholism are hepatic methyltetrahydrofolate/homocysteine methylknown risk factors for carcinogenesis. Supplemental transferase (methionine synthase) activity with comfolic acid improved bronchial dysplasia in smokers, 1 pensatory increase of betaine/homocysteine methylcervical dysplasia in women using oral contraceptives, 2 transferase activity.11-13 Ethanol-induced alterations in folate and methionine metabolism could be relevant to carcinogenesis through decreased availability of Abbreviations: dNTP, deoxynucleoside triphosphate; SAM, S-adenosylmethionine; SAH, S-adenosylhomocysteine; dUTP, deoxyuridine triphosphate; methyl groups for DNA methylation 14 or by altered regdTTP, deoxythymidine triphospha...

Hepatic phospholipids in alcoholic liver disease assessed by proton-decoupled 31P magnetic resonance spectroscopy

“…Besides the fact that the availability of methyl groups and also the activation of methionine to SAM following alcohol ingestion is limited [7,[9][10][11][12][13], an important observation seems to be the inhibition of PEMT by acetaldehyde [7,8].…”

“…Furthermore, chronic alcohol ingestion results in a reduced availability of the methyl groups that are necessary for phosphatidylcholine generation [9]. This disturbed hepatic methyl transfer is a result of various effects of alcohol including folate, vitamin B 12 , and vitamin B 6 deficiencies as well as decreased formation of S-adenosylmethionine (SAM), the active methylating compound [7,[9][10][11][12][13].…”

ER stress: Can the liver cope?

“…Ethanol feeding lowered methionine synthase leading to increased accumulation of 5-methyl tetrahydrofolate and Hcy and to decreased levels of betaine, a product of choline oxidation and the substrate of BHMT [130]. In micropigs fed ethanol for 12 months with adequate folate, MS activity decreased by 20% which was associated with slightly decreased plasma methionine, 20% increased plasma Hcy, and increased hepatic SAH but no change in SAM [131][132][133]. Chronic alcohol increases choline uptake [134] and mitochondrial oxidation to betaine [135] suggesting compensation for increased demand for betaine.…”

Diagnosis and treatment of nutritional deficiencies in alcoholic liver disease: Overview of available evidence and open issues

“…The methionine metabolic pathways are deeply influenced by alcohol consumption and folate deficiency may promote liver disease resulting in defective DNA synthesis and stability, both associated with an increased risk for hepatocellular carcinoma [25] and reduced methylation capacity on the expression of genes related to liver injury [26].…”