Journal article
Human pregnane X receptor: genetic polymorphisms, alternative mRNA splice variants, and cytochrome P450 3A metabolic activity
Journal of clinical pharmacology, Vol.46(11), pp.1356-1369
11/2006
Handle:
https://hdl.handle.net/2376/109469
PMID: 17050801
Abstract
Human pregnane X receptor (hPXR) gene polymorphisms (spanning exon 2 to exon 5) and alternative mRNA splicing were investigated as possible contributors to individual variability in CYP3A metabolic activity measured both in vivo and in vitro. None of the 9 variants evaluated, including the 2 most common nonsynonymous variants (Pro27Ser and Gly36Arg), was found to be associated with midazolam 1'-hydroxylation rate measured in a bank of human livers (48 European Americans, 4 African Americans, 2 Hispanics). In contrast, 3 linked hPXR variants (g.252A > G, g.275A > G, and g.4760G > A) were significantly (P < .05) associated with oral midazolam clearance in a mixed race/ethnicity population (n = 26) and the African American subpopulation (n = 14) but not in European Americans (n = 9). Although the amount of hPXR mRNA normally spliced at the exon 4-5 junction correlated well with midazolam 1'-hydroxylation activities (P < .05), none of the 6 hPXR mRNA splice variants identified was associated with midazolam 1'-hydroxylation. In conclusion, several hPXR polymorphisms have been identified that may have predictive value for oral midazolam clearance, particularly in African Americans.
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Details
- Title
- Human pregnane X receptor: genetic polymorphisms, alternative mRNA splice variants, and cytochrome P450 3A metabolic activity
- Creators
- Ping He - Division of Clinical Pharmacology, Department of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine, Boston, MA 02111, USAMichael H CourtDavid J GreenblattLisa L von Moltke
- Publication Details
- Journal of clinical pharmacology, Vol.46(11), pp.1356-1369
- Academic Unit
- Veterinary Clinical Sciences, Department of
- Publisher
- England
- Grant note
- DK-58496 / NIDDK NIH HHS GM-61834 / NIGMS NIH HHS DA-05258 / NIDA NIH HHS AG-17880 / NIA NIH HHS AI-58784 / NIAID NIH HHS RR-00054 / NCRR NIH HHS AT-01381 / NCCIH NIH HHS GM-74369 / NIGMS NIH HHS DA-13209 / NIDA NIH HHS MH-58435 / NIMH NIH HHS
- Identifiers
- 99900547496501842
- Language
- English
- Resource Type
- Journal article