N-Nitrosodiethylamine genotoxicity in primary rat hepatocytes: Effects of cytochrome P450 induction by phenobarbital
N-Nitrosodiethylamine genotoxicity in primary rat hepatocytes: Effects of cytochrome P450 induction by phenobarbital
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DOI：
10.1016/j.toxlet.2011.07.002
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发表时间：
2011-10-10
影响因子：
3.5
通讯作者：
Eckl, Peter
中科院分区：
文献类型：
--
作者：
Aiub, Claudia A. F.;Gadermaier, Gabriele;Eckl, Peter
原代肝细胞广泛应用于药物代谢及其毒理学效应的研究。在存在苯巴比妥（PB）的情况下，在雌性大鼠肝细胞原代培养物中使用N-亚硝基二乙胺（NDEA）诱导的遗传毒性和细胞毒性。PB预处理（1 mM）增加了NDEA处理（0.21-105 μ g/mL）后坏死（2倍）和凋亡细胞（4倍）的数量。有丝分裂指数和微核细胞数量减少，因此表明具有细胞毒性。PB预处理后，观察到染色体畸变数量增加。NDEA处理（0.21-21 μ g/mL）诱导CYP 2B 1和CYP 2B 2 mRNA的表达，PB单独处理分别诱导CYP 2B 1和CYP 2B 2 mRNA增加6倍和2倍。PB暴露后的NDEA处理在所有测试浓度下均增加CYP 2B 1 mRNA表达，并且在21和105 μ g/mL下也增加CYP 2B 2表达。我们的数据表明，PB对CYP 2B 1/2表达的改变增加了NDEA的细胞毒性和遗传毒性，导致最终的遗传毒性代谢产物。(C)2011爱思唯尔爱尔兰有限公司保留所有权利。
Primary hepatocytes are widely used in investigating drug metabolism and its toxicological effects. N-Nitrosodiethylamine (NDEA)-induced genotoxicity and cytotoxicity was used in primary cultures of female rat hepatocytes in the presence of phenobarbital (PB). PB pre-treatment (1 mM) increased the number of necrotic (2-fold) and apoptotic cells (4-fold) after NDEA treatment (0.21-105 mu g/mL). The mitotic indices and the number of micronucleated cells decreased, thus suggesting cytotoxicity. An increased number of chromosomal aberrations were observed after pre-treatment with PB. NDEA-treatment (0.21-21 mu g/mL) induced expression of the CYP2B1 and CYP2B2 mRNA and PB treatment alone induced similar to 6-fold and similar to 2-fold increases of CYP2B1 and CYP2B2 mRNA, respectively. NDEA treatment following PB exposure increased CYP2B1 mRNA expression under all tested concentrations and also increased CYP2B2 expression at 21 and 105 mu g/mL. Our data suggest that the alteration of CYP2B1/2 expression by PB increased the cytotoxicity and genotoxicity of NDEA leading to the final genotoxic metabolite. (C) 2011 Elsevier Ireland Ltd. All rights reserved.