Response of phenobarbital- and ciprofibrate-exposed hepatocytes to growth factors in type I collagen gels.
The response of promoter-exposed hepatocytes to the complete hepatic mitogens hepatocyte growth factor (HGF), epidermal growth factor (EGF) and acidic fibroblast growth factor (aFGF) was studied. Male Fisher 344 rats were administered phenobarbital or ciprofibrate. Hepatocytes were isolated at various time points and cultured in type I collagen gels, a 3-dimensional culture system that allows stable long-term hepatocyte differentiation. DNA synthetic activity in response to addition of HGF, aFGF or EGF to the cultures was assayed by incorporation of [3H]thymidine. Administration of ciprofibrate to rats caused an immediate decreased growth response in hepatocytes to all three growth factors. Phenobarbital administration caused a gradual decrease in responsiveness to the growth factors: after 10 days, hepatocytes became insensitive to the mitogenic effects of HGF, EGF and aFGF. However, an early increase in responsiveness to HGF and aFGF occurred in phenobarbital-exposed hepatocytes. The results indicate that phenobarbital and ciprofibrate have similar inhibitory effects on hepatocyte DNA synthesis in culture after long-term in vivo exposure. However, their early effects on hepatocyte growth response differ considerably, suggesting that their effects on cellular proliferation occur via different mechanisms.
Lindroos
P
P
Department of Pathology, Duke University, Durham, NC 27710.
Michalopoulos
G K
GK
D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D002995:Clofibric Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D003094:Collagen; D004247:DNA / Q000096:biosynthesis; D004347:Drug Interactions; D004815:Epidermal Growth Factor / Q000494:pharmacology*; D058607:Fibric Acids; D016220:Fibroblast Growth Factor 1 / Q000494:pharmacology*; D017228:Hepatocyte Growth Factor / Q000494:pharmacology*; D008099:Liver / Q000166:cytology / Q000187:drug effects*; D008297:Male; D010634:Phenobarbital / Q000494:pharmacology*; D051381:Rats; D011916:Rats, Inbred F344
D058607:Fibric Acids; D016220:Fibroblast Growth Factor 1; D002995:Clofibric Acid; D004815:Epidermal Growth Factor; D017228:Hepatocyte Growth Factor; D003094:Collagen; D004247:DNA; C019304:ciprofibrate; D010634:Phenobarbital