Suppression by phenobarbital of ethionine-induced hepatocellular carcinoma formation and hepatic S-adenosylethionine levels.

Abstract

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.

• Authors: P T Allen, L A Poirier
• Journal: Carcinogenesis (Carcinogenesis) Vol. 18 Issue 5 Pg. 1103-7 (May 1997) ISSN: 0143-3334 [Print] England
• PMID: 9163702 (Publication Type: Journal Article)

Chemical References

• S-adenosylethionine
• S-Adenosylmethionine
• Adenosine
• Ethionine
• Phenobarbital

Topics

• Adenosine (analogs & derivatives, metabolism)
• Animals
• Body Weight
• Ethionine (administration & dosage, analogs & derivatives, antagonists & inhibitors, metabolism)
• Liver (anatomy & histology, metabolism)
• Liver Neoplasms (chemically induced)
• Male
• Methylation
• Organ Size
• Phenobarbital (administration & dosage)
• Rats
• Rats, Inbred F344
• S-Adenosylmethionine (metabolism)