The inhibition by methionine and choline of liver carcinoma formation in male C3H mice dosed with diethylnitrosamine and fed phenobarbital

Abstract

The ability of the dietary methyl donors methionine and choline to inhibit the carcinogenic and tumor-promoting effects of phenobarbital (PB) in the livers of male weanling C3H mice was examined. The mice were fed a commercial rodent diet with or without 0.05% PB. Thirty animals from each set received the diet with either: (1) no dietary supplementation, (2) an additional 1.0% choline chloride, (3) 1.5% DL-methionine or (4) both 1.5% DL-methionine and 1.0% choline chloride. Additional groups of 30 animals with the same eight dietary and PB-treatment regimens described above were given a single initiating dose of 150 mg diethylnitrosamine (DENA)/kg body wt dissolved in saline, or the saline solution only, 1 week prior to the start of PB feeding. The 16 treatment groups were fed their respective diets for 12 months. Statistical trend analysis showed that increasing levels of supplemental methyl donors gave highly significant protection in PB-treated mice (P less than 0.01). The incidence of liver carcinomas in the four dietary groups not receiving PB or DENA varied from 0 to 7%. The PB-treated animals not receiving an initiating dose of DENA developed hepatocellular carcinomas (HCCs) at incidences of 79% in group 1 animals, 74% in group 2 animals, 60% in group 3 animals, and 31% in group 2 animals respectively. Thus, incidence of HCCs in group 4 was significantly lower than in groups 1, 2 or 3 (P less than 0.01). However, the total incidence of liver tumors (adenomas plus carcinomas) was about the same in all DENA or PB-treated groups. Thus, dietary supplementation with methyl donors increased the proportion of animals bearing liver adenomas as their most advanced hepatic lesion in PB-treated mice. In DENA-treated mice fed PB, dietary supplementation with methionine and choline protected against the formation of liver carcinomas (P less than 0.02); however, methionine and choline had no significant effect on liver tumor formation in mice fed the PB-free diets. Methionine and choline supplementation gave significant protection against HCC metastases in the lungs of the tumor-bearing mice in groups initiated with DENA followed by PB promotion. These results support the hypothesis that PB exerts it tumorigenic activity in mice at least in part through a physiological insufficiency of labile methyl groups.

Nutritional Epigenetics and the Prevention of Hepatocellular Carcinoma with Bioactive Food Constituents

“…Indeed, several research groups have explored this hypothesis. For instance, Fullerton et al (114) demonstrated that long-term dietary supplementation of methionine and choline inhibited diethylnitrosamine (DEN)-induced liver carcinogenesis in mice, and Pascale et al (115) reported similar inhibitory effect of long-term administration of SAM on DEN-induced hepatocarcinogenesis in rats. This finding was confirmed in later independent studies using different models of chemical-induced rat hepatocarcinogenesis (116,117).…”

Constitutive active/androstane receptor promotes hepatocarcinogenesis in a mouse model of non-alcoholic steatohepatitis

“…Furthermore, methionine and choline deficiency following a single initiating carcinogen dose were reported to enhance enzyme-altered pre-neoplastic foci formation in rats (36,37). Fullerton et al (38) reported that dietary supplementation with methionine and choline protected against the formation of liver carcinomas in DEN-treated PB-fed mice. Aberrant methylation, consisting of DNA hypomethylation and/or promoter gene CpG hypermethylation, have been implicated in the development of a variety of solid tumors, including HCCs (37)(38)(39)(40).…”

“…Fullerton et al (38) reported that dietary supplementation with methionine and choline protected against the formation of liver carcinomas in DEN-treated PB-fed mice. Aberrant methylation, consisting of DNA hypomethylation and/or promoter gene CpG hypermethylation, have been implicated in the development of a variety of solid tumors, including HCCs (37)(38)(39)(40). Because methionine and choline deficiency lead to aberrant methylation (37-40), a similar mechanism might be involved in the results observed in the current study.…”

Sixth plot of the carcinogenic potency database: results of animal bioassays published in the General Literature 1989 to 1990 and by the National Toxicology Program 1990 to 1993.

“…We have used the CPDB to address many issues relevant to chemical carcinogenesis and interspecies extrapolation (8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24). Papers published since the fifth plot discuss: how tautological are interspecies correlations of carcinogenic potencies (25); three key factors in mutagenesis and carcinogenesis: DNA lesions, inducible DNA repair, and cell division (26); comparison of target organs of carcinogenicity for mutagenic and nonmutagenic chemicals (27); prediction of carcinogenicity from two instead of four sex-species groups (28); the importance of data on mechanism of carcinogenesis in efforts to predict low-dose human risk (29); comparison of results for heterocyclic amines with other chemicals in the CPDB (30); setting priorities among possible carcinogenic hazards in the workplace (31); causes and prevention of human cancer (32); and quick estimation of the regulatory, virtually safe dose based on the MTD (33).…”