Growth stimulation of primary rat hepatocytes by 2,3,7,8-tetrachlorodibenzo-p-dioxin.
The modulation of liver growth control by the tumor promoter, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), was investigated in primary hepatocytes of adult rats. Under defined conditions in serum-free cultures, the interaction of TCDD with growth-related hormones was studied. TCDD-treatment of the cultured hepatocytes for two days caused a transient stimulation of both DNA synthesis and mitotic activity. This effect was maximal at the very low nontoxic concentration of 10(-12) M TCDD, i.e., two orders of magnitude below the optimal concentrations for induction of drug metabolizing enzymes. Growth stimulation by TCDD was dependent on the presence of growth-related hormones; in primary rat hepatocytes, TCDD acted synergistically with insulin and epidermal growth factor (EGF) and antagonized the growth inhibition by dexamethasone. Under culture conditions allowing high rates of DNA synthesis, e.g., at low concentrations of dexamethasone, in the presence of EGF plus alpha 1-adrenergic agonists or rat serum, no significant effect of TCDD on cellular growth was observed. Furthermore, TCDD failed to stimulate DNA synthesis in a rat hepatoma cell line, H4IIE, which is less sensitive to growth controlling factors than normal hepatocytes. Therefore, the results suggest that the growth modulation of primary rat hepatocytes by TCDD is the most sensitive parameter of the agent thus far observed. This effect may involve both a release from the growth inhibition caused, for instance, by glucocorticoids, as well as a direct growth-stimulating effect, synergistic to the one induced by insulin.
Wölfle
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D
Department of Toxicology, University of Hamburg Medical School, Federal Republic of Germany.
Becker
E
E
Schmutte
C
C
D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D019363:Cytochrome P-450 CYP1A1; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis; D004247:DNA / Q000096:biosynthesis / Q000187:drug effects; D003907:Dexamethasone / Q000037:antagonists & inhibitors / Q000494:pharmacology; D004790:Enzyme Induction / Q000187:drug effects; D004815:Epidermal Growth Factor / Q000502:physiology; D005260:Female; D007328:Insulin / Q000502:physiology; D008099:Liver / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D010088:Oxidoreductases / Q000096:biosynthesis; D011078:Polychlorinated Biphenyls / Q000633:toxicity; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity*; D051381:Rats; D017208:Rats, Wistar; D014407:Tumor Cells, Cultured
D000316:Adrenergic alpha-Agonists; D007328:Insulin; D000072317:Polychlorinated Dibenzodioxins; D004815:Epidermal Growth Factor; D003907:Dexamethasone; D004247:DNA; D003577:Cytochrome P-450 Enzyme System; D011078:Polychlorinated Biphenyls; D010088:Oxidoreductases; D019363:Cytochrome P-450 CYP1A1; C028451:3,4,3',4'-tetrachlorobiphenyl