Department of Experimental and Clinical Pharmacology, Pomeranian Medical University, 70-111 Szczecin, Poland.
Department of Pharmacology, Center of Drug Absorption and Transport, University Medicine Greifswald, 17489 Greifswald, Germany.
Int J Mol Sci. 2023 Feb 25;24(5):4543. doi: 10.3390/ijms24054543.
Hepatic drug metabolizing enzymes (DMEs), whose activity may be affected by liver diseases, are major determinants of drug pharmacokinetics. Hepatitis C liver samples in different functional states, i.e., the Child-Pugh class A ( = 30), B ( = 21) and C ( = 7) were analyzed for protein abundances (LC-MS/MS) and mRNA levels (qRT-PCR) of 9 CYPs and 4 UGTs enzymes. The protein levels of CYP1A1, CYP2B6, CYP2C8, CYP2C9, and CYP2D6 were not affected by the disease. In the Child-Pugh class A livers, a significant up-regulation of UGT1A1 (to 163% of the controls) was observed. The Child-Pugh class B was associated with down-regulation of the protein abundance of CYP2C19 (to 38% of the controls), CYP2E1 (to 54%), CYP3A4 (to 33%), UGT1A3 (to 69%), and UGT2B7 (to 56%). In the Child-Pugh class C livers, CYP1A2 was found to be reduced (to 52%). A significant trend in down-regulation of the protein abundance was documented for CYP1A2, CYP2C9, CYP3A4, CYP2E1, UGT2B7, and UGT2B15. The results of the study demonstrate that DMEs protein abundances in the liver are affected by hepatitis C virus infection and depend on the severity of the disease.
肝药物代谢酶（DMEs）的活性可能受肝脏疾病影响，是药物药代动力学的主要决定因素。分析了不同功能状态（即 Child-Pugh 分级 A [=30]、B [=21]和 C [=7]）的丙型肝炎肝样本的 9 种 CYP 和 4 种 UGT 酶的蛋白丰度（LC-MS/MS）和 mRNA 水平（qRT-PCR）。疾病未影响 CYP1A1、CYP2B6、CYP2C8、CYP2C9 和 CYP2D6 的蛋白水平。在 Child-Pugh 分级 A 肝脏中，观察到 UGT1A1 的显著上调（达到对照组的 163%）。Child-Pugh 分级 B 与 CYP2C19 蛋白丰度下调（至对照组的 38%）、CYP2E1（至 54%）、CYP3A4（至 33%）、UGT1A3（至 69%）和 UGT2B7（至 56%）有关。在 Child-Pugh 分级 C 肝脏中，发现 CYP1A2 减少（至 52%）。CYP1A2、CYP2C9、CYP3A4、CYP2E1、UGT2B7 和 UGT2B15 的蛋白丰度下调呈显著趋势。研究结果表明，丙型肝炎病毒感染影响肝脏中 DMEs 的蛋白丰度，并取决于疾病的严重程度。
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