SUPPRESSION BY PHENOBARBITAL OF ETHIONINE-INDUCED HEPATOCELLULAR-CARCINOMA FORMATION AND HEPATIC S-ADENOSYLETHIONINE LEVELS

An 18-month carcinogenicity study was conducted in male weanling F344 rats (28/group) to examine the effects of the simultaneous feeding of selected concentrations of ethionine and 0.05% phenobarbital in a norm al chow diet. The effects of a 1-6-week feeding of phenobarbital and e thionine on the hepatic levels of the related metabolites S-adenosylme thionine, S-adenosylhomocysteine and S-adenosylethionine were also exa mined. Ethionine at 0.3% or 0.1% induced hepatocellular carcinoma (HCC a) at incidences of 90% (19/21) and 89% (24/27), respectively, Adding phenobarbital to the 0.1% ethionine diet reduced the incidence of HCCa to 36% (10/28) and reduced the number of liver tumor-associated death s occurring prior to terminal sacrifice from 10/27 to 1/28. No hepatic tumors were observed in rats fed 0, 0.003, 0.01, or 0.03% ethionine. Phenobarbital alone or combined with 0.03% ethionine produced no hepat ic tumors. Dietary ethionine at 0.1% reduced the intracellular hepatic level of S-adenosylmethionine to <50% of that seen in control rats. P henobarbital alone had little effect on either S-adenosylmethionine or S-adenosylhomocysteine levels. The combination of phenobarbital and 0 .1% ethionine led to increases in the hepatic levels of S-adenosylmeth ionine of 40-60% after 3 and 6 weeks of feeding, compared to those see n in rats receiving 0.1% ethionine alone. Ethionine feeding resulted i n high levels of S-adenosylethionine in the livers. Combining phenobar bital with ethionine in the diet led to 30-50% reductions in hepatic S -adenosylethionine content. The results indicate that phenobarbital in hibits hepatocarcinogenesis by ethionine, that ethionine may cause HCC a via methyl group insufficiency, and that at levels of less than or e qual to 0.03% ethionine did not show evidence of tumorigenicity.