title: Suppression of cytochrome P450 Cyp1a-1 induction in murine hepatoma 1c1c7 cells by 12-O-tetradecanoylphorbol-13-acetate and inhibitors of protein kinase C.
abstract: Treatment of murine hepatoma 1c1c7 cultures with dibenz[a,c]anthracene (DB[a,c]A)-induced P450 Cyp1a-1, as indicated by analyses of CYP1A1 mRNA and 7-ethoxyresorufin O-deethylase (EROD) activity. Pretreatment of cultures with 12-O-tetradecanoylphorbol-13-acetate (TPA) for as short as 1 h reduced protein kinase C (PKC) activity and resulted in a temporary suppression of EROD induction. The dose-response curves defining the TPA-dependent suppression of EROD induction and PKC down-regulation were very similar, as were the initial kinetics of PKC loss and the times of TPA pretreatment required for suppression of EROD induction. The effects of TPA could not be mimicked by 4 alpha-TPA, an analog incapable of activating and down-regulating PKC. Pretreatment of cultures with the protein kinase inhibitors staurosporine, calphostin C, or H7 resulted in dose-dependent suppressions of EROD induction. However, the suppressive and cytotoxic effects of these agents could be separated from one another in the case of only H7. HA1004, an analog of H7 that inhibits the same spectrum of protein kinases as H7 except for PKC, did not inhibit DB[a,c]A induction of EROD. Pretreatment of cultures with H7, but not HA1004, suppressed the accumulation of CYP1A1 mRNA that normally occurred following treatment with DB[a,c]A. Collectively, these studies suggest that PKC plays a role in the processes involved in the induction of Cyp1a-1.
authors.affiliation: Institute of Chemical Toxicology, Wayne State University, Detroit, Michigan 48201.
authors.forename: J J
authors.initials: JJ
authors.lastname: Reiners
authors.forename: A
authors.initials: A
authors.lastname: Schöller
authors.forename: P
authors.initials: P
authors.lastname: Bischer
authors.forename: A R
authors.initials: AR
authors.lastname: Cantu
authors.forename: A
authors.initials: A
authors.lastname: Pavone
mesh_terms: D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D000470:Alkaloids / Q000494:pharmacology; D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis*; D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction / Q000187:drug effects; D007546:Isoquinolines / Q000494:pharmacology; D008114:Liver Neoplasms, Experimental / Q000201:enzymology*; D009281:Naphthalenes; D010879:Piperazines / Q000494:pharmacology; D011083:Polycyclic Compounds / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D019311:Staurosporine; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
chemical_list: D000470:Alkaloids; D007546:Isoquinolines; D009281:Naphthalenes; D010879:Piperazines; D011083:Polycyclic Compounds; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D003577:Cytochrome P-450 Enzyme System; D011493:Protein Kinase C; D019311:Staurosporine; C058819:calphostin C; D013755:Tetradecanoylphorbol Acetate