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Functional polymorphisms of the human multidrug-resistance gene: multiple sequence variations and correlation of one allele with P-glycoprotein expression and activity in vivo.

ABSTRACT: To evaluate whether alterations in the multidrug-resistance (MDR)-1 gene correlate with intestinal MDR-1 expression and uptake of orally administered P-glycoprotein (PGP) substrates, we analyzed the MDR-1 sequence in 21 volunteers whose PGP expression and function in the duodenum had been determined by Western blots and quantitative immunohistology (n = 21) or by plasma concentrations after orally administered digoxin (n = 8 + 14). We observed a significant correlation of a polymorphism in exon 26 (C3435T) of MDR-1 with expression levels and function of MDR-1. Individuals homozygous for this polymorphism had significantly lower duodenal MDR-1 expression and the highest digoxin plasma levels. Homozygosity for this variant was observed in 24% of our sample population (n = 188). This polymorphism is expected to affect the absorption and tissue concentrations of numerous other substrates of MDR-1.

SUBMITTER: Hoffmeyer S

PROVIDER: S-EPMC16264 | biostudies-literature | 2000 Mar

REPOSITORIES: biostudies-literature

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Functional polymorphisms of the human multidrug-resistance gene: multiple sequence variations and correlation of one allele with P-glycoprotein expression and activity in vivo.

Hoffmeyer S S Burk O O von Richter O O Arnold H P HP Brockmöller J J Johne A A Cascorbi I I Gerloff T T Roots I I Eichelbaum M M Brinkmann U U

Proceedings of the National Academy of Sciences of the United States of America 20000301 7

To evaluate whether alterations in the multidrug-resistance (MDR)-1 gene correlate with intestinal MDR-1 expression and uptake of orally administered P-glycoprotein (PGP) substrates, we analyzed the MDR-1 sequence in 21 volunteers whose PGP expression and function in the duodenum had been determined by Western blots and quantitative immunohistology (n = 21) or by plasma concentrations after orally administered digoxin (n = 8 + 14). We observed a significant correlation of a polymorphism in exon ...[more]

PMID: 10716719

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Project description:BackgroundMultidrug resistance (MDR) is often responsible for the failure of chemotherapy treatment, and current strategies for cancer MDR are not adequately satisfying as to their efficacy and safety. In this study, we sought to determine the anti-MDR effects of ultrasound (US) irradiation and its underlying mechanisms against drug-resistance.MethodsMDR variant MCF-7/ADR cell lines and endothelial cell lines were used to determine the appropriate ultrasound intensity for in vitro experiments. MCF-7/ADR cell and HEPG2/ADM cells were used to assess the anti-MDR effect of US irradiation. Intracellular adriamycin (ADM) accumulation, Cell viability, cell proliferation and cell apoptosis were evaluated after ADM?+?US treatment or ADM treatment alone. MCF-7/ADR xenograft mice were used to investigate the appropriate ultrasound intensity for in vivo experiments and its effect on the long-term prognosis. Underlining mechanisms by which ultrasound exposure reversing MDR phenotype were investigated both in vitro and in vivo.ResultsCombination of ADM and 0.74 W/cm2 US irradiation enhanced ADM intracellular concentration and nuclear accumulation in MCF-7/ADR and HEPG2/ADM cells, compared to those treated with ADM alone. Enhanced cellular ADM uptake and nuclei localization was associated with increased cytotoxicity of ADM to ADM-resistant cells, lower ADM-resistant cell viability and proliferative cell ratio, and higher apoptotic cell ratio. More importantly, US exposure increased the effectiveness of ADM to inhibit tumor growth in MCF-7/ADR xenograft mice. Mechanistically, US exposure promoted ADM accumulation in MDR cells mainly through down-regulation of P-glycoprotein (P-gp), which is dependent on US-induced intracellular reactive oxygen species (ROS) production. US-induced oxidative stress promoted miR-200c-3p and miR-34a-3p expression by forming miR-200c/34a/ZEB1 double-negative feedback loop. Finally, US-induced miR-200c/34a overexpression decreased P-gp expression and reversed MDR phenotype.ConclusionUS irradiation could reverse MDR phenotype by activating ROS-ZEB1-miR200c/34a-P-gp signal pathway. Our findings offer a new and promising strategy for sensitizing cells to combat MDR and to improve the therapeutic index of chemotherapy.

Project description:BACKGROUND:Transcription factor (TF) GAMYB, belonging to MYB family (named after the gene of the avian myeloblastosis virus) is a master gibberellin (GA)-induced regulatory protein that is crucial for development and germination of cereal grain and involved in anther formation. It activates many genes including high-molecular-weight glutenin and ?-amylase gene families. This study presents the first attempt to characterize the rye gene encoding GAMYB in relation to its sequence, polymorphisms, and phenotypic effects. RESULTS:ScGAMYB was mapped on rye chromosome 3R using high-density Diversity Arrays Technology (DArT)/DArTseq-based maps developed in three mapping populations. The ScGAMYB sequences were identified in RNA-seq libraries of four rye inbred lines. The transcriptome used for the search contained almost 151,000 transcripts with a median contig length of 500?nt. The average amount of total base raw data was approximately 9?GB. Comparative analysis of the ScGAMYB sequence revealed its high level of homology to wheat and barley orthologues. Single nucleotide polymorphisms (SNPs) detected among rye inbred lines allowed the development of allele specific-PCR (AS-PCR) markers for ScGAMYB that might be used to detect this gene in wide genetic stocks of rye and triticale. Segregation of the ScGAMYB alleles showed significant relationship with ?-amylase activity (AMY). CONCLUSIONS:The research showed the strong similarity of rye GAMYB sequence to its orthologues in other Graminae and confirmed the position in the genome consistent with the collinearity rule of cereal genomes. Concurrently, the ScGAMYB coding sequence (cds) showed stronger variability (24 SNPs) compared to the analogous region of wheat (5 SNPs) and barley (7 SNPs). The moderate regulatory effect of ScGAMYB on AMY was confirmed, therefore, ScGAMYB was identified as a candidate gene for partial control of ?-amylase production in rye grain. The predicted structural protein change in the aa region 362-372, caused by a single SNP (C/G) at the 1100 position in ScGAMYB cds and single aa sequence change (S/C) at the 367 position, is the likely cause of the differences in the effectiveness of ScGAMYB regulatory function associated with AMY. The development of sequence-based, allele-specific (AS) PCR markers could be useful in research and application.

Dataset Information

Functional polymorphisms of the human multidrug-resistance gene: multiple sequence variations and correlation of one allele with P-glycoprotein expression and activity in vivo.

Publications

Functional polymorphisms of the human multidrug-resistance gene: multiple sequence variations and correlation of one allele with P-glycoprotein expression and activity in vivo.

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