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首页> 外文期刊>Archives of Toxicology >Comparative analysis of phase i and II enzyme activities in 5 hepatic cell lines identifies Huh-7 and HCC-T cells with the highest potential to study drug metabolism
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Comparative analysis of phase i and II enzyme activities in 5 hepatic cell lines identifies Huh-7 and HCC-T cells with the highest potential to study drug metabolism

机译：比较5种肝细胞系中i和II期酶的活性，可以确定研究药物代谢潜力最高的Huh-7和HCC-T细胞

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摘要

Primary human hepatocytes (hHeps) are still gold standard to perform human drug metabolism studies, but their availability is limited by donor organ scarcity. Therefore, hepatoma cell lines are widely used as alternatives, although their phases I and II drug-metabolizing activities are substantially lower compared with hHeps. The major advantage of these cell lines is immediate availability, standardized culture conditions and unlimited life span. Therefore, the aim of this study was to investigate the drug-metabolizing profile of five human hepatoma cell lines (HepG2, Hep3B, HCC-T, HCC-M and Huh-7) over a culture period of 10 passages. Fluorescent-based assays for seven different cytochrome P450 (CYP) isoforms and seven different phase II enzymes were performed and compared with enzymatic activities of hHeps. CYP activities were much lower in the cell lines (5-15% of hHeps), whereas phase II enzyme activities that are involved in buffering oxidative stress (e.g., Glutathione-S-transferase) reached levels comparable with hHeps. Furthermore, phases I and II enzyme activities in hepatoma cell lines vary strongly during culture time. Interestingly, the most constant results were obtained with Huh-7 cells. Huh-7 cells as well as HCC-T cells exhibited a drug-metabolizing profile closest to hHeps between passages two and four. Toxicity studies with Diclofenac, Paracetamol and Verapamil in both cell lines show dose-response characteristics and EC 50 values similar to hHeps. Therefore, we propose that due to the more consistent results throughout the passages, Huh-7 could be an alternative system to the limitedly available hHeps and frequently used HepG2 cell line in the study of drug metabolism.
机译：原代人类肝细胞（hHeps）仍是进行人类药物代谢研究的金标准，但它们的可用性受到供体器官稀缺性的限制。因此，尽管与hHeps相比，它们的I和II期药物代谢活性明显降低，但肝癌细胞系却被广泛用作替代品。这些细胞系的主要优点是立即可用，标准化的培养条件和无限的寿命。因此，本研究的目的是研究10个传代培养期内5种人肝癌细胞系（HepG2，Hep3B，HCC-T，HCC-M和Huh-7）的药物代谢情况。对七个不同的细胞色素P450（CYP）同工型和七个不同的II期酶进行了基于荧光的测定，并与hHeps的酶促活性进行了比较。 CYP活性在细胞系中低得多（为hHeps的5-15％），而与缓冲氧化应激有关的II期酶活性（例如谷胱甘肽S-转移酶）达到了与hHeps相当的水平。此外，肝癌细胞系中的I和II期酶活性在培养时间内变化很大。有趣的是，使用Huh-7细胞获得了最恒定的结果。 Huh-7细胞和HCC-T细胞在第2代和第4代之间表现出最接近hHeps的药物代谢特征。在两种细胞系中用双氯芬酸，扑热息痛和维拉帕米进行的毒性研究表明，剂量反应特征和EC 50值与hHeps相似。因此，我们建议，由于在整个传代过程中获得更一致的结果，Huh-7可能是有限的hHeps和在药物代谢研究中经常使用的HepG2细胞系的替代系统。

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