PHENOBARBITAL INDUCTION OF CYTOCHROME P4501A1 IS REGULATED BY CAMP-DEPENDENT PROTEIN KINASE-MEDIATED SIGNALING PATHWAYS IN RAINBOW-TROUT HEPATOCYTES

Phenobarbital (PB) induces CYP1A1 at the transcriptional level and cau ses nuclear translocation of the aromatic hydrocarbon (Ah) receptor in primary cultures of rainbow trout hepatocytes (1). The results from t his study suggest that PB induction of CYP1A1 in rainbow trout hepatoc ytes is regulated by cAMP-dependent pathways (PKA), whereas TCDD induc tion is not dependent upon PKA. Epinephrine, which increases cAMP leve ls and activates PKA-dependent pathways, was a potent inhibitor of PB induction, while having no effect on TCDD induction of CYP1A1 gene exp ression. When PKA-dependent pathways were inhibited, PB induction of C YP1A1 gene expression was greatly potentiated, whereas TCDD induction was affected to a lesser extent. Inhibitors of calcium-phospholipid-de pendent protein kinase (PKC) had modest or no effect on PB and TCDD in duction of CYP1A1, respectively. Whether the relatively weak-to-no inh ibition of CYP1A1 in response to PKC inhibitors in fish is due to diff erences in the types and levels of PKC isoenzymes, cell permeability, protocol, or the role of PKC in the mechanism of CYP1A1 induction in f ish remains to be established. PB induced persistent and transient inc reases in the intracellular calcium concentration. This may be an impo rtant factor regulating PKC which may have a role in PB-mediated induc tion of CYP1A1 gene transcription. (C) 1996 Academic Press, Inc.