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Chemoprevention of hepatocarcinogenesis: S-adenosyl-L-methionine

Pascale, Rosa Maria and Simile, Maria Maddalena and De Miglio, Maria Rosaria and Feo, Francesco (2002) Chemoprevention of hepatocarcinogenesis: S-adenosyl-L-methionine. Alcohol, Vol. 27 (3), p. 193-198. ISSN 0741-8329. Article.

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DOI: 10.1016/S0741-8329(02)00227-6

Abstract

Accumulation of genetic changes characterizes the progression of cells, initiated by carcinogens, to full malignancy. Various epigenetic mechanisms, such as high polyamine synthesis, aberrant DNA methylation, and production of reactive oxygen species, may favor this process by stimulating growth and inducing DNA damage. We observed a decrease in S-adenosyl-L-methionine (SAM) content in the liver, associated with DNA hypomethylation in rat liver, during the development of preneoplastic foci, and in neoplastic nodules and hepatocellular carcinomas, induced in diethylnitrosamine-initiated rats by “resistant hepatocyte” (RH) protocol. Reconstitution of the methyl donor level in the liver by SAM administration inhibits growth and induces phenotypic reversion and apoptosis of preneoplastic cells. A 6-month SAM treatment results in a sharp and persistent decrease in development of neoplastic nodules, suggesting a long duration of SAM chemopreventive effect. Various observations support the suggestion of a role of DNA methylation in chemoprevention by SAM: (1) Exogenous SAM reconstitutes the SAM pool in preneoplastic and neoplastic liver lesions. (2) DNA methylation is positively correlated with SAM:S-adenosylhomocysteine (SAH) ratio in these lesions. (3) 5-Azacytidine, a DNA methyltransferase inhibitor, inhibits chemoprevention by SAM. (4) c-Ha-ras, c-Ki-ras, and c-myc are hypomethylated and overexpressed in preneoplastic liver. Their expression is inversely correlated with SAM:SAH ratio in SAM-treated rats. (5) S-adenosyl-L-methionine treatment results in overall DNA methylation and partial methylation of these genes. Other possible mechanisms of SAM treatment include inhibition of polyamine synthesis, linked to partial transformation of SAM into 5′-methylthioadenosine (MTA), and antioxidant and antifibrogenic activities of both SAM and MTA.

Item Type:Article
ID Code:4322
Status:Published
Refereed:Yes
Uncontrolled Keywords:S-adenosyl-L-methionine, hepatocarcinogenesis, chemoprevention, dna methylation, 5′-methylthioadenosine, antioxidant effect
Subjects:Area 06 - Scienze mediche > MED/04 Patologia generale
Divisions:001 Università di Sassari > 01 Dipartimenti > Scienze biomediche
Publisher:Elsevier
ISSN:0741-8329
Copyright Holders:© 2002 Elsevier Science Inc.
Deposited On:23 Aug 2010 13:35

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