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 selectedconcentrations of ethionine and 0.05% phenobarbital in a normal chow diet.The effects of a 1-6-week feeding of phenobarbital and ethionine on thehepatic levels of the related metabolites S- adenosylmethionine,S-adenosylhomocysteine and S-adenosylethionine were also examined.Ethionine at 0.3% or 0.1% induced hepatocellular carcinoma (HCCa) atincidences of 90% (19/21) and 89% (24/27), respectively. Addingphenobarbital to the 0.1% ethionine diet reduced the incidence of HCCa to36% (10/28) and reduced the number of liver tumor-associated deathsoccurring prior to terminal sacrifice from 10/27 to 1/28. No hepatic tumorswere observed in rats fed 0, 0.003, 0.01, or 0.03% ethionine. Phenobarbitalalone or combined with 0.03% ethionine produced no hepatic tumors. Dietaryethionine at 0.1% reduced the intracellular hepatic level ofS-adenosylmethionine to <50% of that seen in control rats. Phenobarbitalalone had little effect on either S- adenosylmethionine orS-adenosylhomocysteine levels. The combination of phenobarbital and 0.1%ethionine led to increases in the hepatic levels of S-adenosylmethionine of40-60% after 3 and 6 weeks of feeding, compared to those seen in ratsreceiving 0.1% ethionine alone. Ethionine feeding resulted in high levelsof S-adenosylethionine in the livers. Combining phenobarbital withethionine in the diet led to 30- 50% reductions in hepaticS-adenosylethionine content. The results indicate that phenobarbitalinhibits hepatocarcinogenesis by ethionine, that ethionine may cause HCCavia methyl group insufficiency, and that at levels of < or =0.03%ethionine did not show evidence of tumorigenicity.