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.