Carcinogenesis, Vol 19, 1475-1480, Copyright © 1998 by Oxford University Press
M Kitano, T Ichihara, T Matsuda, H Wanibuchi, S Tamano, A Hagiwara, S Imaoka, Y Funae, T Shirai and S Fukushima
The dose dependence of the hepatopromoting effects of phenobarbital (PB)
was investigated in a rat liver medium-term bioassay (Ito test) to
elucidate a practical threshold level. F344 rats were given a single i.p.
injection of diethylnitrosamine (200 mg/kg body wt) and subjected to
two-thirds partial hepatectomy at week 3. Commencing 2 weeks from the
start, PB at doses of 0, 1, 2, 4, 7.5, 15 or 500 p.p.m. in experiment 1 and
0, 0.01, 0.1 or 0.5 p.p.m. in experiment 2 were fed to the rats for 6
weeks. Experiment 3 was conducted to confirm previous data using the same
medium-term bioassay, with PB at doses of 0, 1, 2, 4, 7.5, 15, 30, 60, 125,
250 or 500 p.p.m. fed to the rats. All surviving animals were killed at
week 8 in these experiments and their livers were immunohistochemically
examined for expression of glutathione S-transferase placental form
(GST-P). Quantitative values for GST-P-positive foci in the liver were
increased dose dependently in rats given 60-500 p.p.m. PB. However, those
for doses in the range 1- 7.5 p.p.m. demonstrated a decrease as compared
with the control group (0 p.p.m.), with significant differences observed
for 1 and 2 p.p.m.. The results for 15-30 and 0.01-0.5 p.p.m. were
comparable with the control values. Examination of transforming growth
factor-alpha (TGF- alpha)-positive foci also produced similar results to
those for GST-P in experiment 1. Immunohistochemical staining of TGF-alpha
and GST-P using serial liver sections demonstrated that the
TGF-alpha-positive foci comprised a sub-population of the GST-P-positive
lesions, being approximately 1/8-1/10th as common in livers of animals
treated with PB. TGF-alpha-positive foci were almost always negative on
immunostaining for TGF-beta. Western blotting for proteins CYP2B1, 2C6 and
3A2 revealed a good correlation between changes in GST-P-positive foci and
CYP3A2 protein expression. The finding of inhibition effects at low doses
of PB confirms the presence of a threshold level for promoting effects by
PB on liver carcinogenesis in rats.
ARTICLES
Presence of a threshold for promoting effects of phenobarbital on diethylnitrosamine-induced hepatic foci in the rat
First Department of Pathology, Osaka City University Medical School, Osaka, Japan.
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