Chemoprevention of hepatocarcinogenesis: S.adenosyl-L-methionine

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-Haras
, c-Kiras
, and cmyc
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