Identification of polymorphisms in the 3'-untranslated region of the human pregnane X receptor (PXR) gene associated with variability in cytochrome P450 3A (CYP3A) metabolism.
Single nucleotide polymorphisms in the 3'-untranslated region (3'UTR) of the human pregnane X receptor (PXR) gene might contribute to interindividual variability in cytochrome P450 3A (CYP3A) activity. Genotype-phenotype associations involving PXR-3'UTR single nucleotide polymorphisms were investigated through in vitro (53 human livers from primarily White donors) and in vivo (26 mainly White or African-American volunteers) studies using midazolam 1'-hydroxylation and midazolam apparent oral clearance (CL/F), respectively, as CYP3A-specific probes. PXR-3'UTR resequencing identified twelve single nucleotide polymorphisms, including two that were novel. Although none of the single nucleotide polymorphisms evaluated were associated with altered midazolam 1'-hydroxylation in the liver bank, both rs3732359 homozygotes and rs3732360 carriers showed 80% higher (p < 0.05) CL/F compared with homozygous reference individuals. These differences in CL/F were even larger (100% and 120% higher, respectively; p < 0.01) when only African-American subjects (n = 14) were considered. Five major haplotypes were identified containing the PXR-3'UTR single nucleotide polymorphisms and previously identified intron single nucleotide polymorphisms. Although CL/F differences were not statistically significant within the entire study cohort, African-American carriers of Haplotype-1 (which includes both rs3732359 and rs3732360 variants) exhibited 70% higher median CL/F compared with African-American non-carriers (p = 0.036). The results identify rs3732359 and rs3732360 as PXR-3'UTR single nucleotide polymorphisms associated with higher CYP3A activity in vivo in African-Americans.
Oleson
L
L
Clinical Pharmacology, Tufts University School of Medicine, 136 Harrison Avenue, Boston, MA 02111, USA.
von Moltke
L L
LL
Greenblatt
D J
DJ
Court
M H
MH
D020413:3' Untranslated Regions; D000328:Adult; D001741:Black or African American / Q000235:genetics; D002460:Cell Line; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D005260:Female; D005787:Gene Frequency; D017930:Genes, Reporter; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D000077297:Pregnane X Receptor; D017433:Protein Structure, Secondary; D012333:RNA, Messenger / Q000378:metabolism; D011987:Receptors, Steroid / Q000235:genetics*; D055815:Young Adult
D020413:3' Untranslated Regions; D000077297:Pregnane X Receptor; D012333:RNA, Messenger; D011987:Receptors, Steroid; D003577:Cytochrome P-450 Enzyme System; D008156:Luciferases; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A