Functional analysis of genetic variations in the 5'-flanking region of the human MDR1 gene.
P-glycoprotein (P-gp), the product of the MDR1 gene, shows large interindividual variations in expression, which leads to differences in the pharmacokinetics of the substrate drugs. The functions of single nucleotide polymorphisms located in the nuclear receptor-responsive element of the 5'-flanking region in the human MDR1 gene were analyzed in order to clarify the mechanism underlying the interindividual variation in P-gp expression. Electrophoretic mobility shift assays revealed that the -7833C>T substitution in the nuclear receptor-responsive region of MDR1 decreases the binding affinities of four nuclear receptors to their responsive elements: vitamin D receptor (VDR), thyroid hormone receptor (TR), constitutive androstane receptor (CAR), and pregnane X receptor (PXR). A reporter gene assay revealed that the C-to-T substitution at -7833 also reduces the transcriptional activation of MDR1 by VDR, TRβ, CAR, and PXR. However, another SNP (-1211T>C substitution), which results in the formation of a xenobiotic responsive element-like sequence and a hypoxia responsive element-like sequence, failed to affect the aryl hydrocarbon receptor-dependent and hypoxia-induced transcriptional activation of MDR1. Although the frequency of the -7833C>T substitution in MDR1 is relatively low, the SNP is crucial because it may alter the pharmacokinetics of P-gp substrates in a small subset of the population.
Saeki
Mayumi
M
Division of Medicinal Safety Science, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan.
Kurose
Kouichi
K
Hasegawa
Ryuichi
R
Tohkin
Masahiro
M
D024506:5' Flanking Region / Q000235:genetics*; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics*; D001483:Base Sequence; D000090702:Constitutive Androstane Receptor; D024202:Electrophoretic Mobility Shift Assay; D017930:Genes, Reporter; D006801:Humans; D008969:Molecular Sequence Data; D020641:Polymorphism, Single Nucleotide; D011119:Polynucleotides / Q000378:metabolism; D000077297:Pregnane X Receptor; D011485:Protein Binding; D018167:Receptors, Calcitriol / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D011987:Receptors, Steroid / Q000378:metabolism; D037042:Thyroid Hormone Receptors beta / Q000378:metabolism; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured
C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000090702:Constitutive Androstane Receptor; D011119:Polynucleotides; D000077297:Pregnane X Receptor; D018167:Receptors, Calcitriol; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D037042:Thyroid Hormone Receptors beta