Related Experiment Videos
Functional polymorphisms of the human multidrug-resistance gene: multiple sequence variations and correlation of one
S Hoffmeyer1, O Burk, O von Richter
1Epidauros Biotechnology, Pharmacogenetics Laboratory, Am Neuland 1, D-82347 Bernried, Germany.
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.
Insights
A common gene variation in the multidrug-resistance (MDR)-1 gene, specifically C3435T, is linked to lower intestinal P-glycoprotein (PGP) expression and higher drug levels in the body.
Area of Science:
- Pharmacogenomics
- Molecular Biology
- Gastroenterology
Background:
- The multidrug-resistance (MDR)-1 gene encodes P-glycoprotein (PGP), a key efflux transporter in the intestine.
- Variations in the MDR-1 gene may influence PGP expression and function, affecting drug absorption and efficacy.
Purpose of the Study:
- To investigate the correlation between MDR-1 gene alterations and intestinal PGP expression and function.
- To assess the impact of MDR-1 variations on the absorption of orally administered PGP substrates like digoxin.
Main Methods:
- Analysis of the MDR-1 gene sequence in 21 volunteers.
- Determination of duodenal PGP expression and function using Western blots and immunohistology.
- Measurement of plasma digoxin concentrations after oral administration.
Main Results:
- A significant correlation was found between the MDR-1 C3435T polymorphism in exon 26 and MDR-1 expression and function.
- Individuals homozygous for the C3435T polymorphism exhibited lower duodenal MDR-1 expression and higher plasma digoxin levels.
- This polymorphism was present in 24% of the studied population (n=188).
Conclusions:
- The MDR-1 C3435T polymorphism significantly impacts intestinal PGP expression and function.
- This genetic variation may affect the absorption and tissue concentrations of various drugs that are PGP substrates.
- Findings suggest implications for personalized medicine and drug therapy.