Phenobarbitone-induced liver response in wild type and in p53 deficient mice.
The tumour suppressor protein, p53, is involved in the regulation of apoptosis and growth arrest following DNA damage. Mutations of the p53 gene are found in 50-55% of all human cancers (Hollstein et al. Nucl. Acid Res. 22 (1994) 3551), including hepatocellular carcinomas. Phenobarbitone (PB) is a non-genotoxic hepatocarcinogen in rats and mice. With commercial availability of mice where one or both alleles of p53 have been removed we have examined the effect of PB in wild type C57BL/6J mice (p53 +/+), and p53 deficient mice (+/- and -/- p53) to determine whether p53 plays a role in the PB induced liver response. In each strain of mice, chronic administration caused liver enlargement, which was associated with centrilobular hepatocyte hypertrophy and a transient hyperplasia. In addition, an increase in centrilobular epidermal growth factor receptor and its ligand, transforming growth factor alpha and a decrease in mannose-6-phosphate receptor and its mitoinhibitory ligand, TGFbeta1 was also observed immunohistochemically. The similar response in all three strains indicates that p53 probably plays no role in the early PB induced liver effects of hypertrophy and changes in growth factor expression.
Gould
S
S
Safety Assessment UK Alderley, AstraZeneca UK Limited, Alderley Park, Macclesfield, SK10 4TG, Cheshire, UK. sarah.gould@astrazeneca.com
Sidaway
J
J
Sansom
N
N
Betton
G
G
Orton
T
T
D000818:Animals; D066246:ErbB Receptors / Q000032:analysis / Q000187:drug effects; D007150:Immunohistochemistry; D008099:Liver / Q000187:drug effects* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009929:Organ Size; D010634:Phenobarbital / Q000633:toxicity*; D016211:Transforming Growth Factor alpha / Q000032:analysis; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*
D016211:Transforming Growth Factor alpha; D016159:Tumor Suppressor Protein p53; D066246:ErbB Receptors; D010634:Phenobarbital