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 alterpatients. 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 feeddemonstrated 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 acalcohol 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 relarge 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 inamong men consuming excessive alcohol and low diversely with methionine synthase activity. These findetary folate 7 and the other showing the greatest inciings were associated with increased frequency of dence of colorectal adenomas in those consuming more hepatocytes with apoptotic bodies and positivity for prothan 30 g alcohol (2 drinks) daily with low intakes of liferating cell nuclear antigen (PCNA) in livers from ethanol-fed minipigs. These studies suggest that chronic foods containing folate or methionine. 8 ethanol feeding perturbs methionine metabolism by im-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, inchemical 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 envidestruction of the folic acid molecule by acetaldehyde, 10 ronment for carcinogenesis during long-term ethanol exthree different groups have shown that long-term posure. (HEPATOLOGY 1996;23:497-505.) ethanol feeding of rats caused significant reduction of Both folate deficiency and chronic alcoholism are hepatic methyltetrahydrofolate/homocy...

Ethanol Lowers Glutathione in Rat Liver and Brain and Inhibits Methionine Synthase in a Cobalamin-Dependent Manner

“…The ability of ETOH to inhibit MS activity has been well-documented (Barak et al, 2002; Halsted et al, 1996; Halsted et al, 2002a; Halsted et al, 2002b), although the underlying mechanism has remained obscure. Decreased MS activity results in accumulation of SAH and inhibition of more than 150 SAM-dependent methylation reactions, with broad cellular consequences (Clarke and Banfield, 2001).…”

“…A number of studies, utilizing different experimental models, have shown that ETOH treatment inhibits MS activity (Barak et al, 2002; Halsted et al, 1996; Halsted et al, 2002a; Halsted et al, 2002b), and it has also been demonstrated that chronic ETOH treatment depletes intracellular GSH in rat liver and brain (Calabrese et al, 1998). Since MeCbl is synthesized in a GSH and SAM-dependent manner (Pezacka et al, 1990), these observations raise the possibility that MS inhibition by ETOH could reflect a limitation in its reactivation due to reduced availability of GSCbl.…”

Zerumbone induced apoptosis in liver cancer cells via modulation of Bax/Bcl-2 ratio

“…The recognition of tumor development involves an imbalance between cell proliferation and apoptotic cell death, which is the current dogma in tumor biology [2]. Evidence showed that hepatocellular apoptosis is essential in all three stages of hepatogenesis, involving the initial genotoxic insult (initiation), through the clonal expansion from a premalignant to a tumorous lesion (promotion) and finally to the progression of tumor growth by further clonal expansion [3]. …”

Alcohol, But Not Lipopolysaccharide‐Induced Liver Apoptosis Involves Changes in Intracellular Compartmentalization of Apoptotic Regulators

“…A LTHOUGH ALCOHOL-INDUCED AUGMENTA-TION of liver apoptosis has been documented both in humans and laboratory animals under in vivo and in vitro settings (Baroni et al, 1994;Benedetti et al, 1988;Bursch et al, 1985;Castaneda and Kinne, 2000;Deaciuc et al, 2001a;Deaciuc et al, 2001b;Deaciuc et al, 2001c;Deaciuc et al, 1999;Deaciuc et al, 2000;Goldin et al, 1993;Halstead et al, 1996;Higuchi et al, 1996;Jiang et al, 1997;Kurose et al, 1997;Müschen et al, 1998;Natori et al, 2001;Neuman et al, 1999;Nobutomo et al, 1998;Pianko et al, 2000;Yacoub et al, 1995;Zhao et al, 1997;Zhou et al, 2001;Ziol et al, 2001), the signaling mechanisms underlying the alcohol effects on apoptosis are incompletely understood. It has become increasingly evident that changes in the rate of apoptosis may lead to diseased conditions.…”