The induction of CYP1A1 by oltipraz is mediated through calcium-dependent-calpain.
The induction of CYP1A1 expression by oltipraz, a synthetic chemo-preventive agent, which increases intracellular calcium concentration, has previously been shown to result from transcriptional activation of CYP1A1 gene mediated by the Ah receptor (AhR), although oltipraz does not bind the receptor. The present study investigated the possible mechanisms of oltipraz-induced activation of AhR and the subsequent induction of CYP1A1 transcription. Treatment of the human metastatic breast cancer cell line MT-2 with oltipraz results in a concentration-dependent increase in the activity of the calcium-dependent calpain, as measured towards the BOC-LM-CMAC fluorescent substrate. This increase in calpain activity was coupled with the AhR activation, as evidenced by its nuclear localization and increased transcription of CYP1A1 gene. Treatment of cells with calpain specific inhibitor MDL 28170 completely blocked the oltipraz-induced nuclear translocation of AhR and subsequent CYP1A1 expression. Furthermore, treatment with oltipraz resulted in the classical ligand-dependent down-regulation of AhR protein, in a concentration dependent manner. The presented data established for the first time a mechanism of activating AhR and its transcription of CYP1A1 by oltipraz through activation of calcium-dependent calpain.
Dale
Yolanda
Y
Graduate Program in Pharmacology, Meharry Medical College, Nashville, TN 37208, USA.
Eltom
Sakina E
SE
D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism*; D002154:Calpain / Q000378:metabolism*; D045744:Cell Line, Tumor; D019363:Cytochrome P-450 CYP1A1 / Q000096:biosynthesis*; D015536:Down-Regulation; D004790:Enzyme Induction / Q000187:drug effects; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008856:Microscopy, Fluorescence; D011719:Pyrazines / Q000494:pharmacology*; D018336:Receptors, Aryl Hydrocarbon / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013871:Thiones; D013876:Thiophenes
D016588:Anticarcinogenic Agents; D011719:Pyrazines; D018336:Receptors, Aryl Hydrocarbon; D013871:Thiones; D013876:Thiophenes; C026209:oltipraz; D019363:Cytochrome P-450 CYP1A1; D002154:Calpain; D002118:Calcium