. Chemoprevention by S-adenosyl-L-methionine of rat liver carcinogenesis initiated by 1,2-dimethylhydrazine and promoted by orotic acid.

Chemoprevention of liver carcinogenesis by S-adenosyl-Lmethionine
(SAM) was studied in F344 male rats. The
rats were given 1,2-dimethylhydrazine (1,2-DMH) 2 HC1
(100 mg/kg, i.p.) 18 h after two-thirds hepatectomy. One
week later they were fed a semisynthetic basal diet containing
1 % orotic acid (OA) for 29 weeks. At this time the
rats were transferred to the basal semisynthetic diet and
were killed 3 weeks later. SAM treatment (384 nmol/kg/
day, i.m.), was started 1 week after 1,2-DMH and was
continued up to the end of the experiment. Controls
received solvent alone. SAM exerted an inhibitory effect
on the induction of preneoplastic and neoplastic lesions.
For example, nodules with diameters of 1-2 and 2-6 mm
exhibited a decrease in both incidence and number per
liver, while no such inhibitory effect was seen in the
category of larger nodules. Furthermore, hepatocellular
carcinoma (HCC) also exhibited a decrease in the SAMtreated
group. The number/liver and incidence were 0.04
and 4.8% respectively in the SAM-treated group, compared
to 0.38 and 37.8% in the control group. Microscopic
examination showed the presence of well-differentiated
carcinomas and atypical nodules in control rats, while only
one small, well-differentiated tumor and one nodule with
patterns of initial transformation were seen in SAM-treated
rats. No patchy staining of glutathione-S-transferase,
indicative of remodeling, was observed in nodules of both
SAM-treated and control rats. Nodules and HCCs developing
in SAM-treated rats exhibited a relatively high number
of apoptotic bodies. Apoptotic bodies count showed 2.8-
and 1.8-fold increases in nodules and HCCs of SAM-treated
rats with respect to controls. These results indicate that
SAM exerts a chemopreventive effect on hepatocarcinogenesis
induced by the OA model. SAM seems to be more
effective in inhibiting nodule to HCC progression than on
the growth of nodule per se. The inhibitory effect is
associated with an increase in cell loss by apoptosis in
nodules and HCC.