| Investigator: | Mary Relling, PharmD |
|---|---|
| Group: | PAAR |
| Genes Studied: | CYP3A, CYP3A4, CYP3A5, NR1I2 |
| Drugs Studied: | midazolam, nifedipine, rifampin, troleandomycin |
| Number of columns (phenotypes): | 14 |
| Number of rows (subjects): | 86 |
Details
The pregnane X receptor (PXR)/steroid and xenobiotic receptor (SXR) transcriptionally activates cytochrome P4503A4 (CYP3A4) when ligand activated by endobiotics and xenobiotics. We cloned the human PXR gene and analysed the sequence in DNAs of individuals whose CYP3A phenotype was known. The PXR gene spans 35 kb, contains nine exons, and mapped to chromosome 13q11-13. Thirty-eight single nucleotide polymorphisms (SNPs) were identified including six SNPs in the coding region. Three of the coding SNPs are non-synonymous creating new PXR alleles [PXR*2, P27S (79C to T); PXR*3, G36R (106G to A); and PXR*4, R122Q (4321G to A)]. The frequency of PXR*2 was 0.20 in African Americans and was never found in Caucasians. Hepatic expression of CYP3A4 protein was not significantly different between African Americans homozygous for PXR*1 compared to those with one PXR*2 allele. PXR*4 was a rare variant found in only one Caucasian person. Homology modelling suggested that R122Q, (PXR*4) is a direct DNA contact site variation in the third alpha-helix in the DNA binding domain. Compared with PXR*1, and variants PXR*2 and PXR*3, only the variant PXR*4 protein had significantly decreased affinity for the PXR binding sequence in electromobility shift assays and attenuated ligand activation of the CYP3A4 reporter plasmids in transient transfection assays. However, the person heterozygous for PXR*4 is normal for CYP3A4 metabolism phenotype. The relevance of each of the 38 PXR SNPs identified in DNA of individuals whose CYP3A basal and rifampin-inducible CYP3A4 expression was determined in vivo and/or in vitro was demonstrated by univariate statistical analysis. Because ligand activation of PXR and upregulation of a system of drug detoxification genes are major determinants of drug interactions, it will now be useful to extend this work to determine the association of these common PXR SNPs to human variation in induction of other drug detoxification gene targets.
Categories of Pharmacogenetic Knowledge
PD
Pharmacodynamics and Drug Response
PK
Pharmacokinetics
FA
Molecular and Cellular Functional Assays
Publications
Primary phenotype data has been submitted and is available
Primary genotype data has been submitted and is available
Literature annotations available
| Relationship | Reference |
|---|---|
|
The human pregnane X receptor: genomic structure and identification and functional characterization of natural allelic variants. Pharmacogenetics. 2001. Zhang J, Kuehl P, Green E D, Touchman J W, Watkins P B, Daly A, Hall S D, Maurel P, Relling M, Brimer C, Yasuda K, Wrighton S A, Hancock M, Kim R B, Strom S, Thummel K, Russell C G, Hudson J R, Schuetz E G, Boguski M S. PMID: 11668216. |
| Subject ID | PharmGKB Accession IDs for subjects in the PharmGKB. |
|---|---|
| Gender | Male, female, or unknown. |
| Race/Ethnicity | Race/Ethnicity as defined by the Office of Management and Budget, followed by the self reported information in parentheses if available. |
| Age | Sample ages have "binned" into 10-year ranges for anonymity. |
| Midazolam hydroxylation (nmol/min/mg prot) | Clearance in nmol/min/mg protein. Blank entries indicate this information was not gathered for these samples. |
| Medication | Medication given to samples (generic names are used, trade names are provided in parentheses if known). OR chart lists the sample received these medications sometime before transplant. Dose/duration/time since last dose/how many doses, etc. are unknown. Blank entries indicate this information was not gathered for these samples. |
| Nifedipine toxicity | Nifedipine toxic = sample received nifedipine and passed out (hypotensive response); No phenotype = sample was not phenotyped. All of the samples with entries for this category are family members. Blank entries indicate this information was not gathered for these samples. |
| Rifampin induction of CYP3A4 (fold change) | Change in sample's intestinal CYP3A4 protein levels after two days of receiving oral rifampin. Blank entries indicate this information was not gathered for these samples. |
| 1-OH midazolam (pmol/min/mg protein) | Formation rate of 1-OH midazolam in kidney microsomes (pmol/min/mg protein). Blank entries indicate this information was not gathered for these samples. |
| CYP3A5 protein expression | Immunoblot analysis with a CYP3A5 antibody was used to call expression as either high or low. Blank entries indicate this information was not gathered for these samples. |
| Exhaled 14C baseline | Baseline amount of exhaled labeled 14C from erythromycin breath test. Blank entries indicate this information was not gathered for these samples. |
| Exhaled 14C TAO | Amount of exhaled labeled 14C-C02 after a single dose of troleandomycin (TAO). Blank entries indicate this information was not gathered for these samples. |
| Exhaled 14C rifampin | Amount of exhaled labeled 14C after a single dose of troleandomycin (TAO) followed by one week of rifampin treatment. Blank entries indicate this information was not gathered for these samples. |
| Nifedipine recovery (%) | Clearance of nifedipine in vivo. Eight hour urinary recovery of nifedipine and metabolites after oral 5 mg nifedipine capsule. Excretion of the M-II metabolite expressed as the percentage recovery of the ingested dose in the 8 hour period. Blank entries indicate this information was not gathered for these samples. |
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