EXPRESSION OF GROWTH-FACTORS AND GROWTH-FACTOR RECEPTORS IN THE LIVEROF C57BL 10J MICE FOLLOWING ADMINISTRATION OF PHENOBARBITONE/

Liver enlargement is a common feature of non-genotoxic rodent hepatoca rcinogens administered at high doses, In the present study, the expres sion of growth factors and growth factor receptors was investigated in the C57BL/10J mouse during liver enlargement induced by the non-genot oxic rodent hepatocarcinogen, sodium phenobarbitone (PB), Male mice we re dosed 0-2500 p.p.m. PB in the diet for 1, 4 and 13 weeks, There was a dose and time dependent increase in liver weight, Hepatocyte replic ation, assessed by incorporation of bromodeoxyuridine, was increased i n a dose-dependent manner at week 1 only (18-fold increase at 2000 p.p .m.) and was predominantly localized in the centrilobular region, At w eek 1, PB (2500 p.p.m.) caused transient increases in transforming gro wth factor alpha (TGF alpha) and epidermal growth factor receptor (EGF R) and decreases in transforming growth factor beta 1 (TGF-beta 1) and mannose-6-phosphate receptor (M6PR) in centrilobular hepatocytes whic h correlated with the replication in this region. At week 1, there was an increase in both hepatocyte growth factor (HGF) and hepatocyte gro wth factor receptor (HGFR) which colocalized in centrilobular hepatocy tes in some mice or periportal hepatocytes in other mice, After 13 wee ks, HGF and HGFR were localized in the cytoplasm of centrilobular hepa tocytes of all mice but exhibited a differential intracellular distrib ution across the lobule, At 2500 p.p.m. PB, EGFR and HGFR mRNA were es sentially unchanged over the 13 week dosing period whilst M6PR mRNA wa s increased 2- to 4-fold, At 2500 p.p.m. PB, EGFR protein levels from immunoblots showed a consistent decrease over the 13 weeks whilst M6PR and HGFR protein levels were essentially unchanged, The protein level and mRNA data for EGFR suggest post-transcriptional modification. Thu s, phenobarbitone caused transient replication of hepatocytes and modu lation of growth stimulatory and inhibitory factors and their associat ed receptors in terms of overall levels and regional distribution in t he liver.