Impact of the haplotypes of the human pregnane X receptor gene on the basal and St John's wort‐induced activity of cytochrome P450 3A4 enzyme

Abstract

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Human pregnane X receptor (PXR/NR1I2) is a key regulator of cytochrome P450 3A4. • To date, there are 198 reported SNPs for the human PXR/NR1I2 gene.• Some of these SNPs are found to affect the inducing ability of PXR to CYP3A4. WHAT THIS STUDY ADDS• This study, for the first time, has investigated the effect of PXR haplotype on basal and St John's wort-induced CYP3A4 activity in humans.• H1/H1 of the PXR gene had weaker basal transcriptional activity but greater inducible transcriptional activity to CYP3A4 than H1/H2 and H2/H2. AIMSHuman pregnane X receptor (PXR/NR1I2) is the master regulator of CYP3A4, which metabolizes >50% of drugs on the market. This study investigated the relationship between the two most frequent haplotypes [H1 (TCAGGGGCCACC) and H2 (CCGAAAACTAAT)] of PXR and basal and St John's wort (SJW)-induced CYP3A4 activity. METHODSTen healthy subjects carrying H1 and H2 haplotypes (three subjects with H1/H1, four with H1/H2 and three with H2/H2) entered this study. The 10 subjects did not carry CYP3A4*4, *5 and *6. All subjects were administrated a 300-mg SJW tablet three times daily for 14 days, and CYP3A4 activity was measured using nifedipine (NIF) as a probe. The plasma concentrations of NIF and dehydronifedipine (DNIF) were determined by a validated liquid chromatography/mass spectrometry/mass spectrometry method. RESULTSAfter administration of SJW, the AUC0-• of NIF decreased significantly, and the AUC0-• of DNIF increased significantly (P < 0.05). For H1/H2, the AUC0-• of NIF decreased by 42.4%, and the AUC0-• of DNIF increased by 20.2%; for H2/H2, the AUC0-• of NIF decreased by 47.9%, and the AUC0-• of DNIF increased by 33.0%; for H1/H1, the AUC0-• of NIF decreased by 29.0%, yet the AUC0-• of DNIF increased by 106.7%. The increase of the AUC0-• of DNIF in H1/H1 was significantly different from the other two haplotype pairs (P < 0.05). Meanwhile, before administration of SJW, the ratio of AUC0-•(DNIF)/AUC0-•(NIF) was the lowest for H1/H1 (22.1%), compared with H1/H2 (58.7%) and H2/H2 (30.0%). CONCLUSIONSH1/H1 of the human PXR gene had weaker basal transcriptional activity but greater inducible transcriptional activity to CYP3A4 than H1/H2 and H2/H2.

Effects of Pregnane X Receptor (NR1I2) and CYP2B6 Genetic Polymorphisms on the Induction of Bupropion Hydroxylation by Rifampin

“…Higher mRNA levels of intestinal CYP3A4 were associated with g.7635G and g.8055T, and greater induction of CYP3A activity was found in Ϫ25385TT subjects than in Ϫ25385CC subjects, as measured by an erythromycin breath test (Zhang et al, 2001). In addition, a recent report showed that the NR1I2 haplotype, including TGT, was associated with weaker basal activity but greater inducible transcriptional activity of CYP3A4, based on a PK study of nifedipine (Wang et al, 2009). However, these studies were performed with CYP3A4 substrates, a very small sample size (n ϭ 3), and limited in vivo PK information regarding the substrate drugs, and, in addition, their associated mechanism has not been experimentally demonstrated.…”

“…The CAC haplotype was the most common and was regarded as the wild-type allele, and the CGT and TGT haplotypes were the primary variant alleles, based on their allele frequencies. Considering that the Ϫ25385CϾT SNP has been reported previously to exhibit altered transcriptional activity (Zhang et al, 2001;Wang et al, 2009), the subjects were divided into TGT carrier (n ϭ 13) and noncarrier (n ϭ 22) groups, based on the existence of the NR1I2 TGT haplotype, as well as the Ϫ25385CϾT SNP.…”

Interactions between Herbs and Conventional Drugs: Overview of the Clinical Data

“…Clinical evidence suggests that St. John’s wort may cause both pharmacokinetic and pharmacodynamic interactions. Using well-established probe drugs, a great number of clinical trials have consistently shown that St. John’s wort induced P-glycoprotein as well as CYP3A4, CYP2E1 and CYP2C19, with no effect on CYP1A2, CYP2D6 or CYP2C9 [144,145,146,147,148,149,150,151,152,153,154,155,156,157]. Induction of CYP enzymes and P-glycoprotein is caused by hyperforin via activation of the pregnane X receptor [158,159,160,161].…”

Polymorphisms in Slco1B3 and Nr1I2 as Genetic Determinants of Hematotoxicity of Carboplatin and Paclitaxel Combination

“…Conversely to carboplatin, paclitaxel exhibits an extensive hepatic metabolism involving phase I enzymes (CYP1B1, CYP3A4, CYP3A5, CYP2C8) and transporters (SLCO1B3, ABCB1, ABCC1, ABCC2) [7,8]. SNPs from the nuclear receptors CAR (NR1I3) and PXR (NR1I2) were also selected because of the crucial role of these genes as ligand-dependent transcription Polymorphisms in SLCO1B3 and NR1I2 as genetic determinants of hematotoxicity of carboplatin and paclitaxel combination 10.2217/PGS. 15.84 Pharmacogenomics (Epub ahead of print) future science group Research Article Mbatchi, Schmitt, Thomas et al factors regulating the expression of many drug-metabolizing enzymes and transporters [9].…”