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MDR1 genotype is associated with hepatic cytochrome P450 3A4 basal and induction phenotype

Jatinder Lamba1, Stephen Strom, Raman Venkataramanan

  • 1Department of Pharmaceutical Sciences, St Jude Children's Research Hospital, Memphis, TN 38105, USA.

Clinical Pharmacology and Therapeutics
|April 4, 2006
PubMed
Abstract

Insights

Genetic variations in the multidrug resistance 1 (MDR1) gene influence cytochrome P450 (CYP) 3A4 expression. The MDR1 2677T allele is linked to higher basal CYP3A4 levels, while the 2677G allele shows greater induction by rifampin.

Area of Science:

  • Pharmacogenomics
  • Drug Metabolism
  • Molecular Biology

Background:

  • Cytochrome P450 (CYP) 3A4 expression varies significantly among individuals, but this variation is not fully explained by CYP3A4 gene variants.
  • Polymorphisms in genes encoding drug transporters and nuclear receptors are potential contributors to this variability.

Purpose of the Study:

  • To investigate the association between common single-nucleotide polymorphisms (SNPs) in the multidrug resistance 1 (MDR1) gene and the pregnane X receptor (PXR) gene with basal and inducible CYP3A4 expression.
  • To determine if MDR1 or PXR genotypes influence CYP3A4 expression in human liver and small intestine.

Main Methods:

  • Genotyping of MDR1 G2677T and C3435T SNPs, and a PXR 6-base pair (bp) deletion in DNA from 144 human livers and 57 small bowel biopsy specimens.
  • Phenotyping of basal or rifampin-inducible CYP3A4 expression and/or activity in these tissues.

Main Results:

  • Homozygosity for the MDR1 2677T allele was associated with significantly higher basal hepatic CYP3A4 expression and activity compared to the 2677G allele, particularly in men.
  • Rifampin induction of CYP3A4 activity was greater in individuals homozygous for the MDR1 2677G allele compared to the 2677T allele.
  • A PXR 6-bp deletion also influenced CYP3A4 expression, with a significant interaction observed between MDR1 2677 SNP and PXR 6-bp deletion.

Conclusions:

  • MDR1 genotype, specifically the 2677T allele, enhances constitutive CYP3A4 expression in the liver and intestine, especially in males.
  • The MDR1 2677G allele is associated with a greater induction of CYP3A4 by rifampin, inversely related to baseline expression.
  • MDR1 genotype may predict basal CYP3A4 levels and the extent of drug interactions, adding complexity to understanding substrate disposition for shared CYP3A4 and MDR1/P-glycoprotein substrates.

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