Non-alcoholic fatty liver disease (NAFLD) - pathogenesis, classification, and effect on drug metabolizing enzymes and transporters.
Non-alcoholic fatty liver disease (NAFLD) - pathogenesis, classification, and effect on drug metabolizing enzymes and transporters.
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非酒精性脂肪肝疾病（NAFLD） - 对药物代谢酶和转运蛋白的发病机理，分类和影响。
DOI：
10.1080/03602532.2017.1293683
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发表时间：
2017-05
影响因子：
5.9
通讯作者：
Akhlaghi F
中科院分区：
文献类型：
--
作者：
Cobbina E;Akhlaghi F
非酒精性脂肪性肝病（NAFLD）是一系列肝脏疾病。它的定义是在超过5%的肝细胞中存在脂肪变性，很少或没有饮酒。胰岛素抵抗、代谢综合征或2型糖尿病以及PNPLA 3或TM 6SF 2的遗传变异似乎在NAFLD的发病机制中起作用。NAFLD的病理进展初步遵循“三击”过程，即脂肪变性、脂毒性和炎症。脂肪变性、氧化应激和炎症介质如TNF-α和IL-6的存在与NAFLD中核因子如CAR、PXR、PPAR-α的改变有关。这些因素可能导致药物代谢酶（DME）或转运蛋白的表达和活性改变。现有证据表明，在啮齿动物和人类研究中，NAFLD对CYP 3A 4、CYP 2 E1和MRP 3的影响更为一致。在NASH中，CYP 3A 4活性下调，而CYP 2 E1和外排转运蛋白MRP 3的活性上调。然而，目前尚不清楚大多数CYP、UGT、SULT和转运蛋白在体内或体外如何受到NAFLD的影响。与NAFLD相关的改变可能是患者药物变异性的潜在来源，并可能对外源性药物的安全性和有效性产生严重影响。本文就NAFLD对主要药物代谢酶和转运蛋白的调节、表达和活性的影响作一综述。我们还讨论了这些变化的潜在机制。
Non-alcoholic fatty liver disease (NAFLD) is a spectrum of liver disorders. It is defined by the presence of steatosis in more than 5 % of hepatocytes with little or no alcohol consumption. Insulin resistance, the metabolic syndrome or type 2 diabetes and genetic variants of PNPLA3 or TM6SF2 seem to play a role in the pathogenesis of NAFLD. The pathological progression of NAFLD follows tentatively a ‘three-hit’ process namely steatosis, lipotoxicity and inflammation. The presence of steatosis, oxidative stress and inflammatory mediators like TNF-α and IL-6 have been implicated in the alterations of nuclear factors such as CAR, PXR, PPAR-α in NAFLD. These factors may results in altered expression and activity of drug metabolizing enzymes (DMEs) or transporters. Existing evidence suggests that the effect of NAFLD on CYP3A4, CYP2E1 and MRP3 are more consistent across rodent and human studies. CYP3A4 activity is down-regulated in NASH whereas the activity of CYP2E1 and the efflux transporter MRP3 are up-regulated. However, it is not clear how the majority of CYPs, UGTs, SULTs and transporters are influenced by NAFLD either in vivo or in vitro. The alterations associated with NAFLD could be a potential source of drug variability in patients and could have serious implications for the safety and efficacy of xenobiotics. In this review, we summarize the effects of NAFLD on the regulation, expression and activity of major drug metabolizing enzymes and transporters. We also discuss the potential mechanisms underlying these alterations.
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在非酒精性脂肪肝疾病中诱导CYP2E1。
影响因子：
3.6
作者：
Aljomah G;Baker SS;Liu W;Kozielski R;Oluwole J;Lupu B;Baker RD;Zhu L
通讯作者：
Zhu L
影响因子：
7.7
作者：
Bell, Ming;Wang, Hong;Chen, Hui;McLenithan, John C.;Gong, Da-Wei;Yang, Rong-Zee;Yu, Daozhan;Fried, Susan K.;Quon, Michael J.;Londos, Constantine;Sztalryd, Carole
通讯作者：
Sztalryd, Carole
影响因子：
13.5
作者：
Browning, JD;Szczepaniak, LS;Hobbs, HH
通讯作者：
Hobbs, HH
影响因子：
37.8
作者：
Alberti, K. G. M. M.;Eckel, Robert H.;Smith, Sidney C., Jr.
通讯作者：
Smith, Sidney C., Jr.
影响因子：
3.9
作者：
Canet, Mark J.;Hardwick, Rhiannon N.;Cherrington, Nathan J.
通讯作者：
Cherrington, Nathan J.