Induction of
proteins involved in
drug metabolism and in
drug delivery has a significant impact on
drug-drug interactions and on the final
therapeutic effects. Two antitumor
acridine derivatives selected for present studies,
C-1748 (9-(2'-hydroxyethylamino)-4-methyl-1-nitroacridine) and
C-1305 (5-dimethylaminopropylamino-8-hydroxy-triazoloacridinone), expressed high and low susceptibility to metabolic transformations with liver microsomes, respectively. In the current study, we examined the influence of these compounds on
cytochrome P450 3A4 (
CYP3A4) and 2C9 (
CYP2C9) enzymatic activity and gene expression in HepG2
tumor cells. Luminescence and HPLC examination, real-time RT-PCR and western blot analyses along with transfection of
pregnane X receptor (PXR)
siRNA and
CYP3A4 reporter gene assays were applied. We found that both compounds strongly induced
CYP3A4 and
CYP2C9 activity and expression as well as expression of UGT1A1 and MDR1 in a concentration- and time-dependent manner. C-1748-mediated
CYP3A4 and
CYP2C9 mRNA induction equal to
rifampicin occurred at extremely low concentrations (0.001 and 0.01μM), whereas 10μM
C-1305 induced three-times higher
CYP3A4 and
CYP2C9 mRNA levels than
rifampicin did.
CYP3A4 and
CYP2C9 expressions were shown to be PXR-dependent; however, neither compound influenced PXR expression. Thus, the observed
drug-mediated induction of
isoenzymes occurs on a PXR-mediated regulatory level. Furthermore,
C-1748 and
C-1305 were demonstrated to be selective PXR agonists. These effects are
hypoxia-inhibited only in the case of
C-1748, which is sensitive to P450 metabolism. In summary, PXR was found to be a new target of the studied compounds. Thus, possible combinations of these compounds with other
therapeutics might lead to the PXR-dependent
enzyme-mediated
drug-drug interactions.