The abilities of the
dihydropyridine calcium channel blocker nicardipine (Nic) to induce
cytochrome P450 1 family
enzymes (CYP1s) and to enhance the
3-methylcholanthrene (MC)-mediated induction of CYP1s and formation of
MC-DNA adduct were examined in the human
hepatoma cell line HepG2. The results from real time RT-PCR analysis demonstrated that Nic could induce CYP1 mRNAs and enhance the MC-mediated induction of the CYP1 mRNAs. The
luciferase-reporter gene assay using the HepG2-A10 cell line, which has been previously established for the screening of
aryl hydrocarbon receptor (AhR) activators, also indicated the augmentation of MC-mediated activation of AhR (induction of
luciferase) by Nic, although Nic showed limited capacity for the activation of AhR. Furthermore, the results from the Western blot analysis of CYP1s, the
enzyme activity assay, and the assay for
MC-DNA adduct formation indicated that Nic could enhance the MC-mediated induction of CYP1s, especially
CYP1A1. Furthermore, the intracellular accumulation level of [(3)H]MC
after treatment of HepG2 cells with [(3)H]MC significantly increased in the presence of Nic. The present findings demonstrate that Nic can enhance the MC-mediated induction of CYP1s, especially
CYP1A1, and the formation of
MC-DNA adduct in HepG2 cells. Furthermore, the augmentation of the MC-mediated bioactivation by Nic is demonstrated to occur mainly through an increase in intracellular accumulation of MC.