N-Nitrosodiethylamine genotoxicity in primary rat hepatocytes: Effects of cytochrome P450 induction by phenobarbital

被引:8
作者
Aiub, Claudia A. F. [1 ]
Gadermaier, Gabriele [2 ]
Oliveira, Izaura [1 ]
Felzenszwalb, Israel [1 ,2 ]
Ferreira, Fatima [2 ]
Ribeiro Pinto, Luis Felipe [3 ,4 ]
Eckl, Peter [5 ]
机构
[1] Rio Janeiro State Univ, Dept Biophys & Biometry, BR-20551030 Rio De Janeiro, Brazil
[2] Salzburg Univ, Dept Mol Biol, A-5020 Salzburg, Austria
[3] Rio Janeiro State Univ, Dept Biochem, BR-20551030 Rio De Janeiro, Brazil
[4] Rio Janeiro State Univ, Div Genet, Brazilian Natl Canc Inst, BR-20551030 Rio De Janeiro, Brazil
[5] Salzburg Univ, Dept Cell Biol, Div Genet, A-5020 Salzburg, Austria
关键词
Genotoxicity; N-Nitrosodiethylamine; Hepatocytes; Phenobarbital; Cytochrome P450 isoforms; NITROSO COMPOUNDS; LIVER-TUMORS; EXPRESSION; NITROSAMINES; MECHANISMS; MODE; RISK;
D O I
10.1016/j.toxlet.2011.07.002
中图分类号
R99 [毒物学(毒理学)];
学科分类号
100405 ;
摘要
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.
引用
收藏
页码:139 / 143
页数:5
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