He Ping, Court Michael H, Greenblatt David J, von Moltke Lisa L
Division of Clinical Pharmacology, Department of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine, Boston, MA 02111, USA.
J Clin Pharmacol. 2006 Nov;46(11):1356-69. doi: 10.1177/0091270006292125.
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.
研究了人类孕烷X受体（hPXR）基因多态性（跨越外显子2至外显子5）和可变mRNA剪接，以探究其是否可能导致体内和体外测量的CYP3A代谢活性存在个体差异。在所评估的9个变体中，包括2个最常见的非同义变体（Pro27Ser和Gly36Arg），均未发现与一组人类肝脏（48名欧裔美国人、4名非裔美国人、2名西班牙裔）中测量的咪达唑仑1'-羟化率相关。相比之下，3个连锁的hPXR变体（g.252A>G、g.275A>G和g.4760G>A）与混合种族/族裔人群（n=26）和非裔美国人亚组（n=14）中的口服咪达唑仑清除率显著相关（P<.05），但在欧裔美国人（n=9）中则不然。虽然通常在外显子4-5连接处剪接的hPXR mRNA量与咪达唑仑1'-羟化活性密切相关（P<.05），但所鉴定的6种hPXR mRNA剪接变体均与咪达唑仑1'-羟化无关。总之，已鉴定出几种hPXR多态性，它们可能对口服咪达唑仑清除率具有预测价值，尤其是在非裔美国人中。
