Veterinary Drugs & Biologics Division, Animal and Plant Quarantine Agency, 480, Anyang 6-dong, Anyang City, Gyeonggi-do, 430-757, Republic of Korea.
Cell Biol Toxicol. 2015 Jun;31(3):149-59. doi: 10.1007/s10565-015-9300-2. Epub 2015 Apr 19.
In the present study, we differentiated hepatocyte-like cells (HLCs) from human adipose tissue-derived mesenchymal stem cells (AT-MSCs). The hepatic differentiation was confirmed by increases in hepatic proteins or genes, the cytochrome P450 (CYP) activities, albumin secretion, and glycogen storage. To determine the developmental toxic effect of arsanilic acid (Ars) and acetaminophen (AAP) on the hepatic development, the differentiating cells were treated with the test chemicals (below IC12.5) from day 4 to day 13. The enzymatic activities of lactate dehydrogenase (LDH), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) did not significantly differ in response to Ars treatment. AAP treatment increased the activities of all enzymes in a dose-dependent manner, significantly at concentrations of 2.5 and 5 mM of AAP. On the expressions of hepatic genes for Ars, the expressions were significantly inhibited by more than 0.5 mM for Albumin (ALB), but only 2.5 mM for α-feto protein (AFP). In the AAP-treated group, the expressions of ALB and AFP were significantly decreased at the concentrations exceeding 0.625 mM. The activities of CYP3A4 were not changed by both treatments. The activities of CYP1A2 were increased by AAP, whereas it was decreased by Ars treatment. In conclusion, AAP could cause serious adverse effects during the hepatic development as compared to Ars.
在本研究中，我们从人脂肪组织来源的间充质干细胞（AT-MSCs）中分化出肝细胞样细胞（HLCs）。通过增加肝蛋白或基因、细胞色素 P450（CYP）活性、白蛋白分泌和糖原储存来确认肝分化。为了确定对氨基苯砷酸（Ars）和醋氨酚（AAP）对肝发育的发育毒性作用，将分化细胞用测试化学品（低于 IC12.5）从第 4 天处理到第 13 天。乳酸脱氢酶（LDH）、丙氨酸氨基转移酶（ALT）和天冬氨酸氨基转移酶（AST）的酶活性对 Ars 处理没有明显差异。AAP 处理以剂量依赖性方式增加所有酶的活性，在 2.5 和 5 mM 的 AAP 浓度下显著增加。对于 Ars 的肝基因表达，白蛋白（ALB）的表达在超过 0.5 mM 的浓度下被显著抑制，但仅在 2.5 mM 的 Ars 浓度下α-胎蛋白（AFP）的表达被显著抑制。在 AAP 处理组中，ALB 和 AFP 的表达在浓度超过 0.625 mM 时显著降低。两种处理均未改变 CYP3A4 的活性。AAP 增加 CYP1A2 的活性，而 Ars 处理降低其活性。总之，与 Ars 相比，AAP 可能在肝发育过程中引起严重的不良影响。
