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

Authors


Dr Min Huang, PhD, Institute of Clinical Pharmacology, School of Pharmaceutical Sciences, Sun Yat-sen University, 74 Zhongshan Road, section 2, Guangzhou 510080, China.
Tel: + 86 20 873 34521
Fax: + 86 20 873 34718
E-mail: huangmin@mail.sysu.edu.cn
and Dr Shu-Feng Zhou, MD, PhD, Division of Chinese Medicine, School of Health Sciences, WHO Collaborating Centre for Traditional Medicine, RMIT University, Victoria, Australia.
Tel: + 61 3 9925 7794
Fax: + 61 3 9925 7178
E-mail: shufeng.zhou@rmit.edu.au

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.

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 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%).

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.

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