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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
Author(s) -
Wang XueDing,
Li JiaLi,
Su QiBiao,
Guan Su,
Chen Jie,
Du Jun,
He YuWen,
Zeng Jun,
Zhang JinXin,
Chen Xiao,
Huang Min,
Zhou ShuFeng
Publication year - 2009
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1111/j.1365-2125.2008.03344.x
Subject(s) - pregnane x receptor , cyp3a4 , basal (medicine) , cytochrome p450 , chemistry , pharmacology , receptor , haplotype , medicine , endocrinology , biology , gene , enzyme , biochemistry , nuclear receptor , genotype , transcription factor , insulin
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. AIMS Human 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. METHODS Ten 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. RESULTS After administration of SJW, the AUC 0–∞ of NIF decreased significantly, and the AUC 0–∞ of DNIF increased significantly ( P < 0.05). For H1/H2, the AUC 0–∞ of NIF decreased by 42.4%, and the AUC 0–∞ of DNIF increased by 20.2%; for H2/H2, the AUC 0–∞ of NIF decreased by 47.9%, and the AUC 0–∞ of DNIF increased by 33.0%; for H1/H1, the AUC 0–∞ of NIF decreased by 29.0%, yet the AUC 0–∞ of DNIF increased by 106.7%. The increase of the AUC 0–∞ 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 AUC 0–∞(DNIF) /AUC 0–∞(NIF) was the lowest for H1/H1 (22.1%), compared with H1/H2 (58.7%) and H2/H2 (30.0%). CONCLUSIONS H1/H1 of the human PXR gene had weaker basal transcriptional activity but greater inducible transcriptional activity to CYP3A4 than H1/H2 and H2/H2.