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

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.

Modest but Variable Effect of Rifampin on Steady-State Plasma Pharmacokinetics of Efavirenz in Healthy African-American and Caucasian Volunteers

“…rs3745274), CYP2B6*16 (rs28399499), CYP2A6*9B (rs8192726), CYP2A6*17 (rs28399454), pregnane X receptor (PXR; NR1I2) 63396C3T single nucleotide polymorphism (SNP) (rs2472677), and constitutive androsane receptor (CAR; NR1I3) G3A SNP (rs2307424) by using Applied Biosystems kits as we previously described. Genotypes for the UGT2B7*2 (rs7439366), UGT2B7*1c (rs28365062), and PXR variants rs3732360C3T were determined by genomic PCR amplification and sequencing as previously described with minor modifications (9,16,31). The SNPs were selected because they have been previously shown to be associated with efavirenz plasma concentrations or effect (18,19,43), as well as CYP3A4 and CYP2B6 activity (12,31).…”

Prediction of tacrolimus metabolism and dosage requirements based on CYP3A4 phenotype and CYP3A5*3 genotype in Chinese renal transplant recipients

“…Intestinal P-glycoprotein (P-gp) is a product of the multidrug resistant 1 (MDR1) gene in humans and limits the bioavailability of Tac via active efflux [2,3] . Importantly, most single nucleotide polymorphisms (SNPs) for CYP3A4 are unable to fully explain the inter-individual variability in CYP3A enzymatic activity [4] . In contrast, the CYP3A5*3 SNP (A6896G) in exon 3 is strongly associated with CYP3A5 expression [5] , and the effect of the CYP3A5*3 allele on the pharmacokinetics of oral Tac has been confirmed by consistently positive results [1,6] .…”

PXR Variants and Artemisinin Use in Vietnamese Subjects: Frequency Distribution and Impact on the Interindividual Variability of CYP3A Induction by Artemisinin

“…The same observation was made for the 10483T¡C SNP, for which there were significantly different frequency distributions for all other described populations (P ϭ Ͻ0.001 to 0.0258) (16). Because the 7635A¡G, 10331A¡G, and 10483T¡C variants have been shown to alter CYP3A4 expression and function (21,34), the significantly different prevalences of these variants in Vietnamese individuals compared with those for individuals of other ethnicities may have consequences for the metabolism of CYP3A4 substrates. In addition, we investigated the impact of individual PXR variants in an artemisinin-exposed subgroup of 14 subjects who are characterized by higher CYP3A induction levels (Table 1).…”

“…However, of note, the prevalence of the PXR variant 10331A¡G among Vietnamese individuals is significantly different from that among Chinese (P ϭ 0.004) and Malay (P ϭ 0.001) populations (25). Moreover, the frequency distribution of the 10331A¡G variant is substantially different from that in Caucasian populations (P ϭ 0.0001 to 0.062) (3,21). The prevalence of the Ϫ4356T¡C variant in our cohort was not different from the frequency in a Caucasian population (P ϭ 0.881) (19).…”