N-亚硝基二乙胺在原代大鼠肝细胞中的遗传毒性：苯巴比妥诱导细胞色素 P450 的作用。
N-Nitrosodiethylamine genotoxicity in primary rat hepatocytes: effects of cytochrome P450 induction by phenobarbital.
机构信息
Department of Biophysics and Biometry, Rio de Janeiro State University, Rio de Janeiro, Brazil.
出版信息
Toxicol Lett. 2011 Oct 10;206(2):139-43. doi: 10.1016/j.toxlet.2011.07.002. Epub 2011 Jul 7.
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 (1mM) increased the number of necrotic (2-fold) and apoptotic cells (4-fold) after NDEA treatment (0.21-105 μg/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 μg/mL) induced expression of the CYP2B1 and CYP2B2 mRNA and PB treatment alone induced ~6-fold and ~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 μg/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.
原代肝细胞广泛应用于研究药物代谢及其毒理学效应。本研究采用雌性大鼠原代肝细胞，在苯巴比妥（PB）存在的情况下，检测 N-亚硝基二乙胺（NDEA）的遗传毒性和细胞毒性。PB 预处理（1mM）后，NDEA 处理（0.21-105μg/mL）可使坏死细胞（增加 2 倍）和凋亡细胞（增加 4 倍）数量增加。有丝分裂指数和微核细胞数量减少，提示细胞毒性。经 PB 预处理后，观察到染色体畸变数量增加。NDEA 处理（0.21-21μg/mL）可诱导 CYP2B1 和 CYP2B2 mRNA 的表达，而 PB 单独处理可分别诱导 CYP2B1 和 CYP2B2 mRNA 增加 6 倍和 2 倍。在所有测试浓度下，NDEA 处理后 PB 暴露均可增加 CYP2B1 mRNA 的表达，并且在 21 和 105μg/mL 时也可增加 CYP2B2 的表达。我们的数据表明，PB 对 CYP2B1/2 表达的改变增加了 NDEA 的细胞毒性和遗传毒性，导致最终遗传毒性代谢物的产生。
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