Human pregnane X receptor: Genetic polymorphisms, alternative mRNA splice variants, and cytochrome P450 3A metabolic activity
Human pregnane X receptor: Genetic polymorphisms, alternative mRNA splice variants, and cytochrome P450 3A metabolic activity
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DOI：
10.1177/0091270006292125
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发表时间：
2006-11-01
影响因子：
2.9
通讯作者：
von Moltke, Lisa L.
中科院分区：
文献类型：
--
作者：
He, Ping;Court, Michael H.;von Moltke, Lisa L.
研究了人孕烷 X 受体 (hPXR) 基因多态性（跨越外显子 2 至外显子 5）和选择性 mRNA 剪接，作为体内和体外测量的 CYP3A 代谢活性个体差异的可能因素。所评估的 9 个变体，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 名欧洲裔美国人、4 名非洲裔美国人、2 名西班牙裔美国人）中测量的咪达唑仑 1'-羟基化率相关。相比之下，3 个连锁 hPXR 变异（g.252A > G、g.275A > G 和 g.4760G > A）与混合种族/族裔人群 (n = 26) 和非洲裔美国人亚群 (n = 14) 中的口服咪达唑仑清除率显着相关 (P < .05)，但与欧洲裔美国人 (n = 9) 中无关。虽然正常情况下在外显子 4-5 连接处剪接的 hPXR mRNA 量与咪达唑仑 1'-羟基化活性密切相关 (P < .05)，但所鉴定的 6 个 hPXR mRNA 剪接变体均与咪达唑仑 1'-羟基化无关。 总之，已鉴定出几种 hPXR 多态性可能对口服咪达唑仑具有预测价值 清关，尤其是非裔美国人。
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.