Glucocorticoid-xenobiotic interactions: Dexamethasone-mediated potentiation of cytochrome P4501A induction by beta-naphthoflavone in a fish hepatoma cell line (PLHC-1)

The induction of CYP1A by the polycyclic aromatic hydrocarbon (PAH)-type inducer beta-naphthoflavone (BNF) in the Poeciliopsis-lucida hepatocellular carcinoma cell line (PLHC-1), and the effects of the glucocorticoid receptor (GR) agonist dexamethasone (DEX) on this response were examined. Dose-response studies revealed that BNF is three orders of magnitude less potent than the planar halogenated aromatic hydrocarbon 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) as an inducer of the CYP1A activity ethoxyresorufin-O-deethylase (EROD), and that the apparent efficacy for the induction by BNF is 50% of that obtained with TCDD. Addition of 10 mu M DEX resulted In potentiation of CYP1A induction at all doses bi. BNF tested. The degree of that potentiation of induction of CYP1A protein levels and EROD activity differed substantially between doses of BNF and at different times of exposure. For example, the maximal degree of potentiation of EROD induction by DEX was 12-fold in PLHC-1 cells treated with 0.1 mu M BNF 19-fold in cells treated with 1 mu M BNF, and 8-fold in cells treated with 10 mu M BNF These maximal degrees of potentiation of EROD induction were obtained after 30 h with 0.1 mu M BNF, 48 h with 1 mu M BNF and 72 h with 10 mu M BNF. These results demonstrate interactions between GR and aryl hydrocarbon receptor pathways that could influence the response of fish to xenobiotic exposure.