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

Abstract

Chemoprevention of liver carcinogenesis by S-adenosyl-L-methionine (SAM) was studied in F344 male rats. The rats were given 1,2-dimethylhydrazine (1,2-DMH) 2 HCl (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 mumol/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 SAM-treated 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.

S-adenosylmethionine and methylthioadenosine are antiapoptotic in cultured rat hepatocytes but proapoptotic in human hepatoma cells

“…AdoMet and MTA prevented the development of liver tumors in different experimental models of hepatocarcinogenesis in vivo, 8,10 and this was associated with the appearance of apoptotic bodies in hepatic nodules. 28 Because AdoMet and MTA are antiapoptotic in primary hepatocytes, we determined their effects in HuH7 cells.…”

“…7 Chemoprevention of liver carcinogenesis induced by a variety of hepatocarcinogens is another remarkable effect of AdoMet. 8 The molecular mechanism(s) of the hepatoprotective and chemopreventive actions of AdoMet is not completely known. Restoration of depleted GSH levels in the hepatocyte has been proposed to play a role in AdoMet's hepatoprotective action.…”

Role of S-adenosyl-L-methionine in liver health and injury

“…40 These findings agree with the reported chemopreventive action of SAMe and MTA in an in vivo model of chemical hepatocarcinogenesis in rats, which was accompanied by an increase of apoptotic bodies in atypical nodules and HCC foci in SAMe-treated animals. 34 We have identified two mechanisms of SAMe's and MTA's differential effect on apoptosis in normal hepatocytes and liver cancer cells thus far. 14,41 Using microarray, we found SAMe treatment induced Bcl-x expression.…”

“…31 When this fall in SAMe after PH was prevented by exogenous SAMe administration, hepatocyte DNA synthesis was inhibited. 24,32 Additionally, exogenous SAMe prevents the development of HCC in rats treated with hepatocarcinogen, 33,34 inhibits the growth of hepatoma cells, 30 and blocks the mitogenic effect of hepatocyte growth factor (HGF) in hepatocytes. 35 Conversely, chronic SAMe depletion in Mat1a (Ϫ/Ϫ) mice is associated with increased proliferating cell nuclear antigen expression and the spontaneous development of HCC.…”

Implication of Bcl-2 family genes in basal and d-amphetamine–induced apoptosis in preneoplastic and neoplastic rat liver lesions

“…1,4,8 Persistent nodules and HCCs are highly susceptible to some apoptosisinducing treatments, which can inhibit their evolution to more malignant stages. 4,9,10 The mechanisms underlying high constitutive apoptosis of chemically induced preneoplastic and neoplastic liver lesions, in vivo, and their susceptibility to apoptosis-inducing treatments have not been adequately investigated so far, though the knowledge of these mechanisms could be useful for new preventive and therapeutic strategies of liver tumors. In vitro cultured hepatocytes from c-myc transgenic mice show increased apoptosis accompanied by increased p53, Bax, and Bak, and decreased Bcl-2 expression.…”