Xenobiotics and the glucocorticoid receptor: additive antagonistic effects on tyrosine aminotransferase activity in rat hepatoma cells.
Methylsulfonyl-PCBs (MeSO2-PCBs) and some fungicides were studied for their functional effects on the glucocorticoid signal transduction in the Reuber rat hepatoma H-II-E-C3 cell line. 4-Substituted MeSO2-PCBs, tolylfluanid and ketoconazole displayed antagonistic effects on dexamethasone-induced tyrosine aminotransferase specific activity (IC50 ranging from 0.7-5.1 microM), but no agonist activity. These substances also had affinity to the mouse glucocorticoid receptor in competition binding studies, indicating that the inhibition of the middle cerebral artery occlusion-activity is indeed mediated by receptor binding. Thus, substances with a structural resemblance with a methyl sulfonyl group, such as the fungicide tolylfluanid, may inhibit glucocorticoid receptor-regulated gene transcription. In co-exposure experiments with three substances, multivariate modelling showed that the inhibitory effect of 4-MeSO2-2,5,6,2',4'-pentachlorobiphenyl (4-MeSO2-CB91), 4-MeSO2-2,3,6,2',4',5'-hexachlorobiphenyl (4-MeSO2-CB149) and tolylfluanid on tyrosine aminotransferase activity was close to additive. Thus, co-exposure to such different chemicals as persistent organic pollutants and pesticides may affect cells additively. Chemical interference with the glucocorticoid hormone system therefore deserves further attention in vivo.
Johansson
Maria
M
Department of Environmental Toxicology, Uppsala University, Norbyvägen 18A, SE-752 36 Uppsala, Sweden. maria.k.johansson@astra.zeneca.com
Johansson
Niklas
N
Lund
Bert-Ove
BO
D000814:Aniline Compounds / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D045744:Cell Line, Tumor; D003627:Data Interpretation, Statistical; D003907:Dexamethasone / Q000494:pharmacology; D004355:Drug Stability; D004357:Drug Synergism; D007654:Ketoconazole / Q000494:pharmacology; D051379:Mice; D011078:Polychlorinated Biphenyls / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D011965:Receptors, Glucocorticoid / Q000037:antagonists & inhibitors / Q000187:drug effects*; D013449:Sulfonamides / Q000737:chemistry / Q000494:pharmacology*; D013997:Time Factors; D014052:Toluidines; D014316:Tritium; D014444:Tyrosine Transaminase / Q000037:antagonists & inhibitors* / Q000187:drug effects / Q000494:pharmacology; D015262:Xenobiotics / Q000494:pharmacology*
D000814:Aniline Compounds; D011965:Receptors, Glucocorticoid; D013449:Sulfonamides; D014052:Toluidines; D015262:Xenobiotics; D014316:Tritium; C070021:N-dichlorofluoromethylthio-N',N'-dimethyl-N-p-tolylsulfamide; D003907:Dexamethasone; D011078:Polychlorinated Biphenyls; D014444:Tyrosine Transaminase; D007654:Ketoconazole