Inter-donor variability of phase I/phase II metabolism of three reference drugs in cryopreserved primary human hepatocytes in suspension and monolayer
Inter-donor variability of phase I/phase II metabolism of three reference drugs in cryopreserved primary human hepatocytes in suspension and monolayer
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DOI：
10.1016/j.tiv.2016.02.013
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发表时间：
2016-06-01
影响因子：
3.2
通讯作者：
Vos, J. Chris
中科院分区：
文献类型：
--
作者：
den Braver-Sewradj, Shalenie P.;den Braver, Michiel W.;Vos, J. Chris
细胞色素P450（CYP）、UDP-葡萄糖醛酸转移酶（UGT）和磺基转移酶（SULT）是代谢清除的最重要酶。因此，在细胞模型中表征给定药物的I相和II相代谢对于充分解释药物代谢在毒性中的作用是重要的。我们研究了与药物性肝损伤（DILI）相关的三种药物，即对乙酰氨基酚（APAP）、双氯芬酸（DF）和托卡朋（TC）在冻存的5名供体原代人肝细胞悬液和单层中的I相（UGT）和II相（UGT和SULT）代谢。包括一般II相底物7-羟基香豆素（7-HC）进行比较。我们的研究结果表明，在接种后的β-内酰胺酶，UGT和SULT活性的降低是底物依赖性的。因此，I相/II相代谢比率受到显著影响，TC单层向I相代谢转变，APAP和DF向II相代谢转变。药物代谢的供体间变异性是显著的，特别是在7-HC或APAP的硫酸化中。由于UGT和SULT代谢可能导致药物的生物活化和/或解毒，I相/II相代谢的比例变化可能对代谢相关毒性产生重要影响。(C)2016爱思唯尔有限公司版权所有
Cytochrome P450s (CYPs), UDP-glucuronosyltransferases (UGTs) and sulfotransferases (SULTs) are the most important enzymes for metabolic clearance. Characterization of phase I and phase II metabolism of a given drug in cellular models is therefore important for an adequate interpretation of the role of drug metabolism in toxicity. We investigated phase I (CYP) and phase II (UGT and SULT) metabolism of three drugs related to drug-induced liver injury (DILI), namely acetaminophen (APAP), diclofenac (DF) and tolcapone (TC), in cryopreserved primary human hepatocytes from 5 donors in suspension and monolayer. The general phase II substrate 7-hydroxycoumarin (7-HC) was included for comparison. Our results show that the decrease in CYP, UGT and SULT activity after plating is substrate dependent. As a consequence the phase I/phase II metabolism ratio is significantly affected, with a shift in monolayer towards phase I metabolism for TC and towards phase II metabolism for APAP and DF. Inter-donor variability in drug metabolism is significant, especially in sulfation of 7-HC or APAP. As CYP, UGT and SULT metabolism may lead to bioactivation and/or detoxification of drugs, a changed ratio in phase I/phase II metabolism may have important consequences for metabolism-related toxicity. (C) 2016 Elsevier Ltd. All rights reserved.