Abstract
This study investigated the effects of pregnane X receptor (PXR/NR1I2) and CYP2B6 genetic variants on sodium ferulate (SF)-mediated induction of bupropion hydroxylation. The pharmacokinetics of bupropion and hydroxybupropion were evaluated after an oral dose of bupropion (150 mg) administered with and without SF pretreatment for 14 days in 33 healthy subjects. The area under the time-concentration curve (AUC) ratio of AUC_hyd (AUC(0-∞) of hydroxybupropion)/AUC_bup (AUC(0-∞) of bupropion) represents the CYP2B6 hydroxylation activity, which was significantly lower in CYP2B6*6 carriers (NR1I2 TGT noncarriers or carriers) than in noncarriers in both the basal and SF-induced states (p-value<0.05). AUC ratio and AUC_hyd of NR1I2 -24113AA variant were markedly lower than GA and GG genotypes (7.5±2.1 versus 14.5±3.3 and 20.6±1.1, and 8873±1431 versus 14,504±2218 and 17,586±1046) in the induced states. However, -24020(-)/(-) variant didn't show significant difference in the induction of CYP2B6 hydroxylation activity by SF compared with other -24020[GAGAAG]/(-) genotypes. NR1I2 TGT haplotype (-25385T+g.7635G+g.8055T) carriers exhibited a significantly decreased AUC ratio, compared with TGT noncarriers, in the basal states (7.6±1.0 versus 9.7±1.0), while this result wasn't observed in CYP2B6*6 noncarriers. Moreover, individuals with complete mutation-type [CYP2B6*6/*6+NR1I2 TGT+ -24113AA+ -24020 (-)/(-)] showed even lower percent difference of AUC ratio (8.7±1.2 versus 39.5±8.2) than those with complete wild-type. In conclusion, it is suggested that NR1I2 variants decrease the bupropion hydroxylation induced by SF treatment, particularly in CYP2B6*6 carriers.Trial RegistrationChiCTR.org ChiCTR-TRC-11001285
Highlights
IntroductionHuman pregnane X receptor (hPXR) may regulate metabolic pathways in response to changes in the environment by appropriate alterations in gene expression of key metabolic enzymes [1]. hPXR is a member of the nuclear receptor superfamily, and encoded by the NR1I2 gene, which is located in the chromosome 13q11-13 and composed of nine exons
Human pregnane X receptor may regulate metabolic pathways in response to changes in the environment by appropriate alterations in gene expression of key metabolic enzymes [1]. hPXR is a member of the nuclear receptor superfamily, and encoded by the NR1I2 gene, which is located in the chromosome 13q11-13 and composed of nine exons
The subjects were divided into TGT carrier (n = 10) and noncarrier (n = 23) groups, based on the existence of NR1I2 TGT haplotype or not
Summary
Human pregnane X receptor (hPXR) may regulate metabolic pathways in response to changes in the environment by appropriate alterations in gene expression of key metabolic enzymes [1]. hPXR is a member of the nuclear receptor superfamily, and encoded by the NR1I2 gene, which is located in the chromosome 13q11-13 and composed of nine exons. HPXR is a member of the nuclear receptor superfamily, and encoded by the NR1I2 gene, which is located in the chromosome 13q11-13 and composed of nine exons. It consists of 434 amino acids with a molecular weight of 49.7 kDa [2]. It is abundantly expressed in liver and intestine, and plays an important role in ligand-activated transcription and regulation of genes involved in xenobiotic and endobiotic metabolism [3,4,5]. HPXR binds to DNA response elements as a heterodimer with the 9-cis retinoid X receptor (RXRa) [12] and acts as a transcriptional regulator of many important genes that are encoding drug-metabolizing enzymes, such as phase I enzymes (e.g., CYP3A4, 3A5, 2A6, 2B6, 2C9, 2C19, and 1A1), phase II enzymes (e.g., UGT1A1, 1A3, 1A4, and 1A6), and phase III enzymes (e.g., MDR1, MRP2, and OATP1B1) [13,14,15]
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