J Clin Pharmacol
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PHARMACOGENOMICS

Human Pregnane X Receptor: Genetic Polymorphisms, Alternative mRNA Splice Variants, and Cytochrome P450 3A Metabolic Activity

Ping He, Michael H. Court, David J. Greenblatt and Lisa L. von Moltke

From the Division of Clinical Pharmacology (Dr He, Dr Greenblatt, Dr von Moltke) and the Comparative and Molecular Pharmacogenetics Laboratory (Dr Court), Department of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine and Tufts-New England Medical Center, Boston, Massachusetts.

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.

Key Words: hPXR • SNP • splice variant • CYP3A metabolic activity

Address for reprints: Dr. David J. Greenblatt, Department of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine, 136 Harrison Avenue, Boston, MA 02111; e-mail: dj.greenblatt{at}tufts.edu.




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