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.
BACKGROUND
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.


CONCLUSIONS
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.


OBJECTIVE
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-infinity) of NIF decreased significantly, and the AUC(0-infinity) of DNIF increased significantly (P < 0.05). For H1/H2, the AUC(0-infinity) of NIF decreased by 42.4%, and the AUC(0-infinity) of DNIF increased by 20.2%; for H2/H2, the AUC(0-infinity) of NIF decreased by 47.9%, and the AUC(0-infinity) of DNIF increased by 33.0%; for H1/H1, the AUC(0-infinity) of NIF decreased by 29.0%, yet the AUC(0-infinity) of DNIF increased by 106.7%. The increase of the AUC(0-infinity) 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-infinity(DNIF))/AUC(0-infinity(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.
Wang
Xue-Ding
XD
Institute of Clinical Pharmacology, School of Pharmaceutical Sciences, Department of Pharmacy, the First Affiliated Hospital, Sun Yat-sen University, 74 Zhongshan Road, section 2, Guangzhou, China.
Li
Jia-Li
JL
Su
Qi-Biao
QB
Guan
Su
S
Chen
Jie
J
Du
Jun
J
He
Yu-Wen
YW
Zeng
Jun
J
Zhang
Jin-Xin
JX
Chen
Xiao
X
Huang
Min
M
Zhou
Shu-Feng
SF
D000873:Anthracenes; D019540:Area Under Curve; D001643:Bridged Bicyclo Compounds / Q000627:therapeutic use; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D005260:Female; D006239:Haplotypes / Q000502:physiology; D006801:Humans; D020902:Hypericum; D008297:Male; D010569:Perylene / Q000031:analogs & derivatives / Q000627:therapeutic use; D010696:Phloroglucinol / Q000031:analogs & derivatives / Q000627:therapeutic use; D028321:Plant Preparations / Q000494:pharmacology*; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid / Q000235:genetics*; D013729:Terpenes / Q000627:therapeutic use; D055815:Young Adult
D000873:Anthracenes; D001643:Bridged Bicyclo Compounds; C000625852:NR1I2 protein, human; D028321:Plant Preparations; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid; D013729:Terpenes; D010569:Perylene; C004965:hypericin; D010696:Phloroglucinol; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; C001654:hyperforin