Human pregnane X receptor: Genetic polymorphisms, alternative mRNA splice variants, and cytochrome P450 3A metabolic activity

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), 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. ©2006 the American College of Clinical Pharmacology.