Significant transcriptional down-regulation of the human MDR1 gene by β-naphthoflavone: A proposed hypothesis linking potent CYP gene induction to MDR1 inhibition

SummaryPrevious work has established the existence of a co-ordinate response in induction between Phase I xenobiotic metabolism, cytochrome P450 (CYP) and the multidrug resistance (MDR1) genes in hepatocytes and some tumor cells. Further correlation was obtained between development of multidrug resistance in cancer cells and a concomitant decrease in inducibility of CYP1A and CYP3A drug metabolizing genes. In the present study, a human MDR1 promoter reporter gene construct was designed to investigate the reverse effect in which selected activators of the major CYP (1–3) genes were tested for potential inhibition of transcriptional activity of the MDR1 gene. β-naphthoflavone (BNF), a potent CYP1A1 inducer, significantly (P < 0.05) down-regulated MDR1 transcriptional activity at 10 μM concentration, causing a 33-fold decrease relative to vector control values. Chemotherapeutic relevance of BNF’s transcriptional down-regulation of MDR1 promoter activity was further demonstrated by its restoring 45.86%, and 79.34% drug sensitivity to the resistant MCF-7/Adr cells at 10- and 20 μM concentrations, respectively (P < 0.05). A functional linkage between potent induction of the major CYP (1–3) genes and transcriptional down-regulation of MDR1 gene in drug-resistant tumor cells is hereby hypothesized. Steroid and xenobiotic nuclear receptor (SXR) is proposed to mediate the cross-talk between the two genes and to recruit potent CYP gene inducers as co-repressor ligands in effecting its transcriptional down-regulation of MDR1 gene. Implications for the multidrug resistance phenomenon are discussed.