Role of high-fat diet in regulation of gene expression of drug metabolizing enzymes and transporters.
Role of high-fat diet in regulation of gene expression of drug metabolizing enzymes and transporters.
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DOI：
10.1016/j.lfs.2011.05.005
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发表时间：
2011-07-04
期刊：
影响因子：
6.1
通讯作者：
Guo, Tao
中科院分区：
文献类型：
--
作者：
Ghose, Romi;Omoluabi, Ozozoma;Gandhi, Adarsh;Shah, Pranav;Strohacker, Kelley;Carpenter, Katie C.;McFarlin, Brian;Guo, Tao
本研究旨在探讨药物代谢酶和转运体基因表达调控在饮食诱导肥胖中的分子机制。成年雄性CD 1小鼠饲喂含60%千卡脂肪（HFD）或10%千卡脂肪（LFD）的饲料14周。通过实时PCR分析肝DME、转运蛋白及其调节性核受体（NR）的RNA水平。在肝脏中测量细胞信号传导组分（JNK和NF-κB）和促炎细胞因子（IL-1β、IL-6和TNFα）的活化。最后，药物代谢的DME的药效学进行了测量，以确定我们的研究结果的临床相关性。与LFD小鼠相比，HFD小鼠肝脏I相（Cyp 3a 11、Cyp 2b 10、Cyp 2a 4）和II相（Ugt 1a 1、Sult 1a 1、Sultn）酶的RNA水平降低约30-60%。Cyp 2 e1、Cyp 1a 2和药物转运蛋白、多药耐药蛋白（Mrp）2、Mrp 3和多药耐药基因（Mdr）1b的RNA水平在HFD小鼠中没有改变。HFD小鼠中NR、PXR和CAR的基因表达以及RXRα的核蛋白水平降低。在HFD小鼠中诱导细胞因子、JNK和NF-κB。因此，肥胖症中肝脏基因表达的减少可能受到NR和炎症诱导的细胞信号传导之间的串扰的调节。咪达唑仑（Cyp 3a底物）在HFD小鼠中的睡眠时间延长，而唑唑胺（Cyp 1a 2和Cyp 2 e1底物）诱导的睡眠时间不变。这项研究表明，DME的基因特异性减少可以影响这些酶代谢的特定药物，从而为监测肥胖患者药物治疗的有效性提供了理论依据。
Our aim is to investigate the molecular mechanism of regulation of gene expression of drug metabolizing enzymes (DMEs) and transporters in diet-induced obesity. Adult male CD1 mice were fed diet containing 60% kcal fat (HFD) or 10% kcal fat (LFD) for 14 weeks. RNA levels of hepatic DMEs, transporters and their regulatory nuclear receptors (NRs) were analyzed by real-time PCR. Activation of cell-signaling components (JNK and NF-κB) and pro-inflammatory cytokines (IL-1β, IL-6 and TNFα) were measured in the liver. Finally, the pharmacodynamics of drugs metabolized by DMEs was measured to determine the clinical relevance of our findings. RNA levels of the hepatic phase I (Cyp3a11, Cyp2b10, Cyp2a4) and phase II (Ugt1a1, Sult1a1, Sultn) enzymes were reduced ~30-60% in HFD compared to LFD mice. RNA levels of Cyp2e1, Cyp1a2 and the drug transporters, multidrug resistance proteins, (Mrp)2, Mrp3 and multidrug resistant gene (Mdr)1b were unaltered in HFD mice. Gene expression of the NRs, PXR and CAR and nuclear protein levels of RXRα was reduced in HFD mice. Cytokines, JNK and NF-κB were induced in HFD mice. Thus reduction in hepatic gene expression in obesity may be modulated by cross-talk between NRs and inflammation-induced cell-signaling. Sleep time of Midazolam (Cyp3a substrate) was prolonged in HFD mice, while Zoxazolamine (Cyp1a2 and Cyp2e1 substrate)-induced sleep time was unaltered. This study demonstrates that gene-specific reductions in DMEs can affect specific drugs metabolized by these enzymes, thus providing a rationale to monitor the effectiveness of drug therapy in obese individuals.
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影响因子：
5.9
作者：
Pascussi, JM;Dvorák, Z;Vilarem, MJ
通讯作者：
Vilarem, MJ
影响因子：
3.9
作者：
Chen, C;Staudinger, JL;Klaassen, CD
通讯作者：
Klaassen, CD
影响因子：
2.4
作者：
Breslin, W. L.;Strohacker, K.;McFarlin, Brian K.
通讯作者：
McFarlin, Brian K.
影响因子：
5.8
作者：
Khemawoot, Phisit;Yokogawa, Koichi;Miyamoto, Ken-ichi
通讯作者：
Miyamoto, Ken-ichi
DOI：
10.1073/pnas.93.4.1671
发表时间：
1996-02-20
影响因子：
11.1
作者：
Liang, HCL;Li, H;Nebert, DW
通讯作者：
Nebert, DW