Journal article
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
Xenobiotica, Vol.40(2), pp.146-162
02/2010
Handle:
https://hdl.handle.net/2376/110419
PMCID: PMC3786868
PMID: 20082578
Abstract
Single nucleotide polymorphisms (SNPs) in the 3′untranslated region (3′UTR) of human pregnane X receptor (
PXR
) gene may contribute to interindividual variability in cytochrome P450 3A (CYP3A) activity.
Genotype-phenotype associations involving
PXR
-3′UTR SNPs were investigated through
in vitro
(53 human livers from primarily white donors) and
in vivo
(26 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 12 SNPs, including 2 that were novel. Although none of the SNPs 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 SNPs and previously identified intron SNPs. 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).
Our results identify rs3732359 and rs3732360 as
PXR
-3′UTR SNPs associated with higher CYP3A activity
in vivo
in African-Americans.
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Details
- Title
- 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
- Creators
- Lauren OlesonLisa L von MoltkeDavid J GreenblattMichael H Court
- Publication Details
- Xenobiotica, Vol.40(2), pp.146-162
- Academic Unit
- Veterinary Clinical Sciences, Department of
- Grant note
- R01 AG017880-05 || AG / National Institute on Aging : NIA F31 DA023861-01 || DA / National Institute on Drug Abuse : NIDA R01 GM061834-08 || GM / National Institute of General Medical Sciences : NIGMS R21 AI058784-02 || AI / National Institute of Allergy and Infectious Diseases Extramural Activities : NIAID
- Identifiers
- 99900547022201842
- Language
- English
- Resource Type
- Journal article