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 normal chow diet. The effects of a 1-6-week feeding of phenobarbital and ethionine on the hepatic 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) 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 deaths 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 hepatic tumors. Dietary ethionine at 0.1% reduced the intracellular hepatic level of S-adenosylmethionine to <50% of that seen in control rats. Phenobarbital 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-adenosylmethionine of 40-60% after 3 and 6 weeks of feeding, compared to those seen in rats receiving 0.1% ethionine alone. Ethionine feeding resulted in high levels of S-adenosylethionine in the livers. Combining phenobarbital with ethionine in the diet led to 30-50% reductions in hepatic S-adenosylethionine content. The results indicate that phenobarbital inhibits hepatocarcinogenesis by ethionine, that ethionine may cause HCCa via methyl group insufficiency, and that at levels of < or =0.03% ethionine did not show evidence of tumorigenicity.
Allen
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PT
National Center for Toxicological Research, Division of Nutritional Toxicology, Jefferson, AR 72079, USA.
Poirier
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LA
D000241:Adenosine / Q000031:analogs & derivatives* / Q000378:metabolism; D000818:Animals; D001835:Body Weight; D005001:Ethionine / Q000008:administration & dosage* / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000378:metabolism; D008099:Liver / Q000033:anatomy & histology / Q000378:metabolism*; D008113:Liver Neoplasms / Q000139:chemically induced*; D008297:Male; D008745:Methylation; D009929:Organ Size; D010634:Phenobarbital / Q000008:administration & dosage*; D051381:Rats; D011916:Rats, Inbred F344; D012436:S-Adenosylmethionine / Q000378:metabolism
C012167:S-adenosylethionine; D012436:S-Adenosylmethionine; D000241:Adenosine; D005001:Ethionine; D010634:Phenobarbital