Xenobiotics and the glucocorticoid receptor: Additive antagonistic effects on tyrosine aminotransferase activity in rat hepatoma cells

Abstract

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 MeSO 2-PCBs, tolylfluanid and ketoconazole displayed antagonistic effects on dexamethasone-induced tyrosine aminotransferase specific activity (IC 50 ranging from 0.7-5.1 μM), 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. © Basic & Clinical Pharmacology & Toxicology 2005.