Human pregnane X receptor: genetic polymorphisms, alternative mRNA splice variants, and cytochrome P450 3A metabolic activity.
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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Ping
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Division of Clinical Pharmacology, Department of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine, Boston, MA 02111, USA.
Court
Michael H
MH
Greenblatt
David J
DJ
von Moltke
Lisa L
LL
D000328:Adult; D001741:Black or African American; D017398:Alternative Splicing / Q000235:genetics*; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006801:Humans; D008099:Liver / Q000378:metabolism; D008297:Male; D008874:Midazolam / Q000378:metabolism; D008875:Middle Aged; D011110:Polymorphism, Genetic; D000077297:Pregnane X Receptor; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism*; D011987:Receptors, Steroid / Q000235:genetics* / Q000378:metabolism*; D044465:White People
D000077297:Pregnane X Receptor; D020033:Protein Isoforms; D012333:RNA, Messenger; D011987:Receptors, Steroid; D003577:Cytochrome P-450 Enzyme System; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; D008874:Midazolam