Characterization of Maternal and Fetal CYP3A-Mediated Progesterone Metabolism.
Characterization of Maternal and Fetal CYP3A-Mediated Progesterone Metabolism.
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DOI：
10.1080/15513815.2017.1354411
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发表时间：
2017-10
影响因子：
1.1
通讯作者：
Patil AS
中科院分区：
文献类型：
--
作者：
Quinney SK;Benjamin T;Zheng X;Patil AS
预后对于维持妊娠和分娩的开始至关重要。我们评估了CYP 450介导的孕酮代谢，特别是CYP 3A亚型的贡献。在含和不含选择性细胞色素P450抑制剂的人肝微粒体（HLM）以及重组CYP 3A 4、CYP 3A 5和CYP 3A 7中表征了体外孕酮代谢。通过HPLC/UV定量6β-羟孕酮（6β-OHP）和16α-羟孕酮（16α-OHP）代谢产物，并拟合Michaelis-Menten方程以确定Km和Vmax。通过体外体内外推法测定CYP 3A 5表达对孕酮清除率的影响。酮康唑对6β-OHP和16α-OHP的抑制率均大于90%。CYP 3A 4产生的6β-OHP和16α-OHP（分别为2.3和1.3 μL/min/pmol）均大于CYP 3A 5（0.09和0.003 μL/min/pmol）和CYP 3A 7（0.004和0.003 μL/min/pmol）。母体通过肝脏CYP 450清除孕酮主要由CYP 3A 4驱动，CYP 3A 5和CYP 3A 7的贡献有限。
Progesterone is critical for maintaining pregnancy and onset of labor. We evaluated CYP450-mediated progesterone metabolism, specifically the contribution of CYP3A isoforms. In vitro progesterone metabolism was characterized in human liver microsomes (HLMs) with and without selective cytochrome P450 inhibitors and in recombinant CYP3A4, CYP3A5, and CYP3A7. 6β-hydroxyprogesterone (6β-OHP) and 16α-hydroxyprogesterone (16α-OHP) metabolites were quantified by HPLC/UV and fit to the Michaelis-Menten equation to determine Km and Vmax. The effect of CYP3A5 expression on progesterone clearance was determined by in vitro in vivo extrapolation. Ketoconazole inhibited formation of both 6β-OHP and 16α-OHP more than 90%. 6β-OHP and 16α-OHP were both produced by CYP3A4 (2.3 and 1.3 μL/min/pmol, respectively) to a greater extent than by CYP3A5 (0.09 and 0.003 μL/min/pmol) and CYP3A7 (0.004 and 0.003 μL/min/pmol). Maternal clearance of progesterone by hepatic CYP450’s is driven primarily by CYP3A4, with limited contributions from CYP3A5 and CYP3A7.
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妊娠中CYP3A底物的半机械代谢模型：预测咪达唑仑和硝苯地平药代动力学的变化。
影响因子：
3.5
作者：
Quinney, S K;Mohamed, A N;Hebert, M F;Haas, D M;Clark, S;Umans, J G;Caritis, S N;Li, L
通讯作者：
Li, L
DOI：
10.1016/s1470-0328(03)02541-2
发表时间：
2003-06-01
影响因子：
5.8
作者：
Astle, S;Khan, RN;Thornton, S
通讯作者：
Thornton, S
DOI：
10.1073/pnas.1633616100
发表时间：
2003-08-05
影响因子：
11.1
作者：
Condon, JC;Jeyasuria, P;Mendelson, CR
通讯作者：
Mendelson, CR
影响因子：
30.8
作者：
Kuehl, P;Zhang, J;Schuetz, E
通讯作者：
Schuetz, E
影响因子：
7.1
作者：
Hassan, S. S.;Romero, R.;Creasy, G. W.
通讯作者：
Creasy, G. W.