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

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.

• Authors: Joseph O Nwankwo
• Journal: Medical hypotheses (Med Hypotheses) Vol. 68 Issue 3 Pg. 661-9 ( 2007) ISSN: 0306-9877 [Print] United States
• PMID: 17011724 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• ATP Binding Cassette Transporter, Subfamily B, Member 1
• beta-Naphthoflavone
• Doxorubicin
• Cytochrome P-450 CYP1A1
• Cytochrome P-450 CYP3A

Topics

• 3T3 Cells
• ATP Binding Cassette Transporter, Subfamily B, Member 1 (drug effects, genetics)
• Animals
• Breast Neoplasms
• Cell Line, Tumor
• Cytochrome P-450 CYP1A1 (biosynthesis, genetics)
• Cytochrome P-450 CYP3A (biosynthesis, genetics)
• Doxorubicin (pharmacology)
• Enzyme Activation (drug effects)
• Female
• Gene Expression Regulation (drug effects)
• Humans
• Kinetics
• Mice
• Promoter Regions, Genetic
• Transcription, Genetic (drug effects)
• Transcriptional Activation
• Transfection
• beta-Naphthoflavone (pharmacology)