Chlorpromazine inhibits the glucocorticoid receptor-mediated gene transcription in a calcium-dependent manner.
Antipsychotic drugs can modulate transcription factors and also nuclear receptors, but their action on glucocorticoid receptors (GR)-members of the steroid/thyroid hormone receptor family has not been studied so far. In the present study we investigated effects of various antipsychotics on the glucocorticoid-mediated gene transcription in fibroblast cells, stably transfected with a mouse mammary tumor virus promoter (LMCAT cells). Chlorpromazine (3-100 microM) inhibited the corticosterone-induced gene transcription in a concentration- and time-dependent manner. Clozapine showed a similar, but less potent effect, while haloperidol acted only in high concentrations, and other antipsychotic drugs (sulpiride, raclopride, remoxipride) were without any effect. It was also found that a phorbol ester (an activator of protein kinase C (PKC)) and A-23187 (Ca(2+)-ionophore) attenuated the inhibitory effect of chlorpromazine on the GR-induced gene transcription. An antagonist of the L-type Ca(2+) channel, as well as an inhibitor of phospholipase C (PLC) inhibited the corticosterone-induced gene transcription, but had no effect on the chlorpromazine-induced changes. The involvement of a PKC/PLC pathway in the chlorpromazine action was confirmed by Western blot analysis which showed that the drug in question decreased the PLC-beta(1) protein level, and to a lesser extent that of the PKC-alpha protein in LMCAT cells. The aforementioned data suggest that inhibition of the glucocorticosteroid-induced gene transcription by chlorpromazine and clozapine may be a mechanism by which these drugs block some effects induced by glucocorticoids. The inhibitory effect of chlorpromazine on the corticosterone-induced gene transcription seems to depend on the inhibition of Ca(2+) influx and/or the inhibition of some calcium-dependent enzymes, e.g. phospholipase beta(1).
Basta-Kaim
A
A
Department of Endocrinology, Institute of Pharmacology, Polish Academy of Sciences, 12 Smetna Street, 31-343 Kraków, Poland.
Budziszewska
B
B
Jaworska-Feil
L
L
Tetich
M
M
Leśkiewicz
M
M
Kubera
M
M
Lasoń
W
W
D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D000001:Calcimycin / Q000494:pharmacology; D002118:Calcium / Q000494:pharmacology*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002460:Cell Line; D002461:Cell Line, Transformed; D015500:Chloramphenicol O-Acetyltransferase / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D002746:Chlorpromazine / Q000494:pharmacology*; D003024:Clozapine / Q000494:pharmacology; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000031:analogs & derivatives* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004963:Estrenes / Q000494:pharmacology; D005347:Fibroblasts; D005786:Gene Expression Regulation; D017930:Genes, Reporter / Q000187:drug effects / Q000502:physiology; D006220:Haloperidol / Q000494:pharmacology; D006632:Histamine / Q000494:pharmacology; D006634:Histamine H1 Antagonists / Q000494:pharmacology; D007476:Ionophores / Q000494:pharmacology; D008324:Mammary Tumor Virus, Mouse; D051379:Mice; D009543:Nifedipine / Q000494:pharmacology; D010703:Phorbol Esters / Q000494:pharmacology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D011493:Protein Kinase C / Q000187:drug effects / Q000378:metabolism; D051571:Protein Kinase C-alpha; D011738:Pyrilamine / Q000494:pharmacology; D011760:Pyrrolidinones / Q000494:pharmacology; D020891:Raclopride / Q000494:pharmacology; D011965:Receptors, Glucocorticoid / Q000187:drug effects / Q000502:physiology*; D017330:Remoxipride / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology; D013469:Sulpiride / Q000494:pharmacology; D013755:Tetradecanoylphorbol Acetate / Q000031:analogs & derivatives* / Q000494:pharmacology; D013873:Thionucleotides / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects*; D010738:Type C Phospholipases / Q000187:drug effects / Q000378:metabolism
D014150:Antipsychotic Agents; D002121:Calcium Channel Blockers; D004791:Enzyme Inhibitors; D004963:Estrenes; D006634:Histamine H1 Antagonists; D007476:Ionophores; D010703:Phorbol Esters; D010726:Phosphodiesterase Inhibitors; D011760:Pyrrolidinones; D011965:Receptors, Glucocorticoid; D013449:Sulfonamides; D013873:Thionucleotides; D017330:Remoxipride; C060229:1-(6-((3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione; D005576:Colforsin; C016957:adenosine-3',5'-cyclic phosphorothioate; D000001:Calcimycin; D020891:Raclopride; C020922:4-O-methyl-12-O-tetradecanoylphorbol 13-acetate; D013469:Sulpiride; C033772:N-(4-aminobutyl)-5-chloro-2-naphthalenesulfonamide; D006632:Histamine; D000242:Cyclic AMP; D015500:Chloramphenicol O-Acetyltransferase; C496630:Prkca protein, mouse; D011493:Protein Kinase C; D051571:Protein Kinase C-alpha; D010738:Type C Phospholipases; D011738:Pyrilamine; D009543:Nifedipine; D003024:Clozapine; D006220:Haloperidol; D013755:Tetradecanoylphorbol Acetate; D002118:Calcium; D002746:Chlorpromazine