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  • Title: Significant transcriptional down-regulation of the human MDR1 gene by beta-naphthoflavone: a proposed hypothesis linking potent CYP gene induction to MDR1 inhibition.
    Author: Nwankwo JO.
    Journal: Med Hypotheses; 2007; 68(3):661-9. PubMed ID: 17011724.
    Abstract:
    Previous 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. beta-naphthoflavone (BNF), a potent CYP1A1 inducer, significantly (P<0.05) down-regulated MDR1 transcriptional activity at 10 microM 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 microM 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.
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