Effect of chronic phenobarbitone administration on liver tumour formation in the C57BL/10J mouse.
The hepatocarcinogenicity of sodium phenobarbitone (PB) was studied in male and female mice of the low spontaneous liver tumour incidence C57BL/10 J strain. Treatment with 200 and 1000 ppmPB for 1 month increased relative liver weight in both sexes, with 1000 ppmPB also producing a transient increase in replicative DNA synthesis. The treatment of male and female mice with 200 and 1000 ppm (the maximum tolerated dose) PB for 99 weeks resulted in centrilobular hypertrophy and a dose-dependent increase in relative liver weight. Altered hepatic foci were observed in both sexes given 1000 ppm PB. In male mice given 1000 ppm PB significant increases were observed in the incidence of hepatocellular adenoma and carcinoma, to 43% and 10% of the animals examined, respectively. No increase in liver tumours was observed in male mice given 200 ppm PB and in female mice given 200 and 1000 ppm PB. In summary, PB at a dose level which produces liver hypertrophy, a transient stimulation of replicative DNA synthesis and on chronic administration altered hepatic foci, three key events in the established mode of action for PB-induced rodent liver tumour formation, results in a significant increase in liver tumours in male C57BL/10 J mice.
Jones
Huw B
HB
Pathology Department, Safety Assessment, AstraZeneca, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom. huw.jones@astrazeneca.com
Orton
Terry C
TC
Lake
Brian G
BG
D000818:Animals; D001835:Body Weight / Q000187:drug effects; D004261:DNA Replication / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005260:Female; D022781:Hepatocytes / Q000187:drug effects; D006993:Hypnotics and Sedatives / Q000633:toxicity*; D008099:Liver / Q000473:pathology; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced* / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009929:Organ Size / Q000187:drug effects; D010634:Phenobarbital / Q000633:toxicity*
D006993:Hypnotics and Sedatives; D010634:Phenobarbital