PMID- 19686823 OWN - NLM STAT- MEDLINE DCOM- 20091130 LR - 20161125 IS - 1879-3169 (Electronic) IS - 0378-4274 (Linking) VI - 191 IP - 1 DP - 2009 Dec 1 TI - Cytotoxicity and mitochondrial dysfunction of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in isolated rat hepatocytes. PG - 79-87 LID - 10.1016/j.toxlet.2009.08.008 [doi] AB - 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is an environmental contaminant that induces hepatic and extrahepatic oxidative stress and the mechanisms of TCDD-induced reactive oxygen species are not fully investigated. Moreover, the potential toxicity of TCDD in isolated rat hepatocytes is not fully explored. The aim of the current study was to explore the possible cytotoxic effect of TCDD on primary rat hepatocytes and to explore the impact of mitochondria in TCDD-induced toxicity. Hepatocytes were isolated from adult rat liver and incubated with 0, 5, 10 or 15 nM of TCDD for 24, 48 and 72 h. Cell viability, lactate dehydrogenase (LDH) leakage into media along with reactive oxygen species (ROS) generation and hydrogen peroxide (H(2)O(2)) production, mitochondrial membrane potential (Deltapsi(m)), superoxide dismutase (SOD), catalse (CAT), glutathione peroxidase (GPx), glutathione reductase (GR), total thiol contents, hepatic aryl hydrocarbon hydroxylase (AHH), and ethoxyresorufin O-deethylase (EROD) were performed in hepatocytes. In addition, superoxide anion generation, lipid peroxidation (LPO), mitochondrial protein carbonyl content and respiratory chain complexes II and IV were assayed in hepatocyte mitochondria. Cell viability was significantly decreased while LDH leakage into media was significantly increased in a dose and time related manner. ROS generation and H(2)O(2) production along with EROD and AHH activities were significantly increased in hepatocytes in the same pattern. The antioxidant enzymes SOD, CAT, GPx and GR and the non-enzymatic protein thiols, in addition to Deltapsi(m) were significantly decreased in hepatocytes in a concentration and time dependent pattern. On the other side, mitochondrial superoxide anion along with LPO and mitochondrial protein carbonyl content were significantly increased while the respiratory chain complexes II and IV activities were significantly decreased in hepatocyte mitochondria. This effect may lead to disruption in the functional integrity of hepatocytes and hepatocyte mitochondria. In conclusion, our data clearly show that TCDD induces hepatocyte toxicity and mitochondrial dysfunction by a mechanism involving generation of ROS. Mitochondria might be the primary source of (or at least contribute to) the oxidative stress response and resulting toxicological outcomes elicited by TCDD. FAU - Aly, Hamdy A A AU - Aly HA AD - Department of Pharmacology and Toxicology, Faculty of Pharmacy, Al-Azhar University, Nasr City, Cairo, Egypt. hamdyaali@yahoo.com FAU - Domenech, Oscar AU - Domenech O LA - eng PT - Journal Article DEP - 20090815 PL - Netherlands TA - Toxicol Lett JT - Toxicology letters JID - 7709027 RN - 0 (Antioxidants) RN - 0 (Environmental Pollutants) RN - 0 (Oxidants) RN - 0 (Polychlorinated Dibenzodioxins) RN - 0 (Reactive Oxygen Species) RN - 0 (Sulfhydryl Compounds) RN - 11062-77-4 (Superoxides) RN - BBX060AN9V (Hydrogen Peroxide) RN - EC 1.14.14.1 (Aryl Hydrocarbon Hydroxylases) RN - EC 1.14.14.1 (Cytochrome P-450 CYP1A1) SB - IM MH - Animals MH - Antioxidants/metabolism MH - Aryl Hydrocarbon Hydroxylases/metabolism MH - Cell Separation MH - Cell Survival/drug effects MH - Cytochrome P-450 CYP1A1/metabolism MH - Electron Transport/drug effects MH - Environmental Pollutants/*toxicity MH - Hepatocytes/drug effects/*metabolism MH - Hydrogen Peroxide/metabolism MH - Lipid Peroxidation/drug effects MH - Male MH - Membrane Potentials/drug effects MH - Mitochondria, Liver/drug effects/*metabolism MH - Oxidants/metabolism MH - Polychlorinated Dibenzodioxins/*toxicity MH - Protein Carbonylation/drug effects MH - Rats MH - Rats, Wistar MH - Reactive Oxygen Species/metabolism MH - Sulfhydryl Compounds/metabolism MH - Superoxides/metabolism EDAT- 2009/08/19 09:00 MHDA- 2009/12/16 06:00 CRDT- 2009/08/19 09:00 PHST- 2009/06/22 00:00 [received] PHST- 2009/08/03 00:00 [revised] PHST- 2009/08/06 00:00 [accepted] PHST- 2009/08/19 09:00 [entrez] PHST- 2009/08/19 09:00 [pubmed] PHST- 2009/12/16 06:00 [medline] AID - S0378-4274(09)01390-3 [pii] AID - 10.1016/j.toxlet.2009.08.008 [doi] PST - ppublish SO - Toxicol Lett. 2009 Dec 1;191(1):79-87. doi: 10.1016/j.toxlet.2009.08.008. Epub 2009 Aug 15.