Abundance of Phase 1 and 2 Drug-Metabolizing Enzymes in Alcoholic and Hepatitis C Cirrhotic Livers: A Quantitative Targeted Proteomics Study
Abundance of Phase 1 and 2 Drug-Metabolizing Enzymes in Alcoholic and Hepatitis C Cirrhotic Livers: A Quantitative Targeted Proteomics Study
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DOI：
10.1124/dmd.118.080523
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发表时间：
2018-07-01
影响因子：
3.9
通讯作者：
Unadkat, Jashvant D.
中科院分区：
文献类型：
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作者：
Prasad, Bhagwat;Bhatt, Deepak Kumar;Unadkat, Jashvant D.
为了使用基于生理学的药代动力学（PBPK）模型预测肝硬化对肝脏药物清除率的影响，我们比较了酒精性（n = 27）或丙型肝炎（HCV，n = 30）肝硬化与非酒精性（对照）肝脏（n = 25）S9组分中各种1相和2相药物代谢酶（DME）的蛋白丰度。酒精或HCV感染的肝脏中S9总蛋白含量显著低于对照肝脏（即，38.3分别为+/- 8.3、32.3 +/- 12.8和51.1 +/- 20.7 mg/g肝脏）。总的来说，酒精性肝硬化与DME丰度的下降幅度大于HCV肝硬化相关;然而，酒精性肝硬化与HCV肝硬化相比，只有UGT 1A 4、乙醇脱氢酶（ADH）1A和ADH 1B的丰度显著降低。当标准化为每克组织时，酒精性肝硬化中的9种DME（UGT 1A 6、UGT 1A 4、CYP 3A 4、UGT 2B 7、CYP 1A 2、ADH 1A、ADH 1B、醛氧化酶（AOX）1和羧酸酯酶（CES）1）和HCV肝硬化中的5种DME（UGT 1A 6、UGT 1A 4、CYP 3A 4、UGT 2B 7和CYP 1A 2）的丰度<对照肝脏中的丰度的25%。大多数DME在异位肝脏中的丰度是对照肝脏的25%至50%。CES 2丰度不受肝硬化的影响。在Simcyp的肝硬化（Child Pugh C）模型中整合肝硬化患者中UGT 2B 7丰度可改善Child Pugh C肝硬化受试者中齐多夫定和吗啡PK的预测。这些数据表明，蛋白质丰度数据，结合PBPK建模和模拟，可以成为一个强大的工具，预测药物在特殊人群中的处置。
To predict the impact of liver cirrhosis on hepatic drug clearance using physiologically based pharmacokinetic (PBPK) modeling, we compared the protein abundance of various phase 1 and phase 2 drug- metabolizing enzymes (DMEs) in S9 fractions of alcoholic (n = 27) or hepatitis C (HCV, n = 30) cirrhotic versus noncirrhotic (control) livers (n = 25). The S9 total protein content was significantly lower in alcoholic or HCV cirrhotic versus control livers (i.e., 38.3 +/- 8.3, 32.3 +/- 12.8, vs. 51.1 +/- 20.7 mg/g liver, respectively). In general, alcoholic cirrhosis was associated with a larger decrease in the DME abundance than HCV cirrhosis; however, only the abundance of UGT1A4, alcohol dehydrogenase (ADH)1A, and ADH1B was significantly lower in alcoholic versus HCV cirrhotic livers. When normalized to per gram of tissue, the abundance of nine DMEs (UGT1A6, UGT1A4, CYP3A4, UGT2B7, CYP1A2, ADH1A, ADH1B, aldehyde oxidase (AOX) 1, and carboxylesterase (CES) 1) in alcoholic cirrhosis and five DMEs (UGT1A6, UGT1A4, CYP3A4, UGT2B7, and CYP1A2) in HCV cirrhosis was < 25% of that in control livers. The abundance of most DMEs in cirrhotic livers was 25% to 50% of control livers. CES2 abundance was not affected by cirrhosis. Integration of UGT2B7 abundance in cirrhotic livers into the liver cirrhosis (Child Pugh C) model of Simcyp improved the prediction of zidovudine and morphine PK in subjects with Child Pugh C liver cirrhosis. These data demonstrate that protein abundance data, combined with PBPK modeling and simulation, can be a powerful tool to predict drug disposition in special populations.