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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.

Proceedings of the National Academy of Sciences of the United States of America
|March 15, 2000
PubMed

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.

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