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首页> 外文期刊>The Journal of Clinical Pharmacology: Official Journal of the American College of Clinical Pharmacology >Human pregnane X receptor: genetic polymorphisms, alternative mRNA splice variants, and cytochrome P450 3A metabolic activity.
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Human pregnane X receptor: genetic polymorphisms, alternative mRNA splice variants, and cytochrome P450 3A metabolic activity.

机译:人孕X受体:遗传多态性,替代的mRNA剪接变体和细胞色素P450 3A代谢活性。

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摘要

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 midazolam1'-hydroxylation. In conclusion, several hPXR polymorphisms have been identified that may have predictive value for oral midazolam clearance, particularly in African Americans.
机译:研究了人类孕烷X受体(hPXR)基因多态性(跨越第2外显子至第5外显子)和可能的mRNA拼接,这可能是导致体内和体外CYP3A代谢活性个体差异的原因。没有发现评估的9个变体,包括2个最常见的非同义变体(Pro27Ser和Gly36Arg),与在人类肝脏中测得的咪达唑仑1'-羟基化率有关(48个欧洲裔美国人,4个非裔美国人,2个西班牙裔)。相反,在种族/民族混合人群中,3个连锁的hPXR变体(g.252A> G,g.275A> G和g.4760G> A)与口服咪达唑仑清除率显着相关(P <.05)(n = 26)和非裔美国人亚群(n = 14),但在欧洲裔美国人中则没有(n = 9)。尽管通常在外显子4-5连接处剪接的hPXR mRNA的量与咪达唑仑1'-羟基化活性相关性很好(P <.05),但鉴定出的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,对口服咪达唑仑清除可能具有预测价值,尤其是在非洲裔美国人中。

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