Significant transcriptional down-regulation of the human MDR1 gene by beta-naphthoflavone: a proposed hypothesis linking potent CYP gene induction to MDR1 inhibition.
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.
Nwankwo
Joseph O
JO
University of Wisconsin Medical School, Surgical Oncology Section, Department of Surgery, K4/619 Clinical Science Center, 600 Highland Avenue, Madison, WI 53792-7375, United States. nwankwo@surgery.wisc.edu
D016475:3T3 Cells; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000187:drug effects / Q000235:genetics*; D000818:Animals; D001943:Breast Neoplasms; D045744:Cell Line, Tumor; D019363:Cytochrome P-450 CYP1A1 / Q000096:biosynthesis / Q000235:genetics*; D051544:Cytochrome P-450 CYP3A / Q000096:biosynthesis / Q000235:genetics*; D004317:Doxorubicin / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D007700:Kinetics; D051379:Mice; D011401:Promoter Regions, Genetic; D014158:Transcription, Genetic / Q000187:drug effects*; D015533:Transcriptional Activation; D014162:Transfection; D019324:beta-Naphthoflavone / Q000494:pharmacology*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D019324:beta-Naphthoflavone; D004317:Doxorubicin; D019363:Cytochrome P-450 CYP1A1; D051544:Cytochrome P-450 CYP3A