ABSTRACT
The carcinogenic effects of estragole in mice of the earlier unexplored strain ICR has been studied. It has been shown that there is a distinct correlation between the extent of inhibition of glucocorticoid-mediated induction of tyrosine aminotransferase and trypthophan oxygenase after acute administration of estragole and the frequency of liver tumors after estragole exposure. Estragole inhibits the induction of these enzymes only in female mice, but not in male mice and rats. DNA-binding activities of liver-enriched transcription factors were investigated on carcinogen-susceptible and -resistant animals. Estragole decreases the HNF4 (hepatic nuclear factor 4) and FOXA DNA-binding activities only in susceptible female mice, but not in nonsusceptible male mice and rats and does not influence the C/EBP and HNF1 activities. Pentachlorophenol, which prevents the hepatocarcinogenic effect of estragole, abolishes its inhibitory effect on tyrosine aminotransferase and trypthophan oxygenase glucocorticoid induction and restores the FOXA and HNF4 DNA-binding activities. The parallelism between the hepatocarcinogenic effects of estragole and the inhibition of FOXA and HNF4 DNA-binding activities serves as an additional argument for the involvement of these factors in the mechanisms of tumor suppression in the liver.
Subject(s)
Anisoles/toxicity , Carcinogens/toxicity , Glucocorticoids/pharmacology , Hepatocyte Nuclear Factor 4/metabolism , Liver Neoplasms/metabolism , Liver/enzymology , Neoplasm Proteins/metabolism , Allylbenzene Derivatives , Animals , Enzyme Induction/drug effects , Enzyme Inhibitors/pharmacology , Female , Liver Neoplasms/chemically induced , Male , Mice , Mice, Inbred ICR , Organ Specificity/drug effects , Pentachlorophenol/pharmacology , Rats , Rats, Wistar , Sex CharacteristicsABSTRACT
o-Aminoazotoluene (OAT) suppressed more than twofold the glucocorticoid induction of tyrosine aminotransferase (TAT) in the liver of SWR mice, which are sensitive to the hepatocarcinogenic effect of OAT, but not in resistant AKR mice. The hormone- and DNA-binding activities of the glucocorticoid receptor (GR) were not affected in either line. The OAT-dependent suppression proved to be associated with a decrease in the DNA-binding activity of HNF3 in liver cell extracts. The content of the HNF3 mRNA did not change, suggesting a posttranscriptional effect of OAT.
