title: Overexpression of Aldose Reductase Render Mouse Hepatocytes More Sensitive to Acetaminophen Induced Oxidative Stress and Cell Death.
abstract: Acetaminophen (APAP) a commonly used drug for decrease the fever and pain but is capable to induced hepatotoxicity at over dose. This study was carried out to investigate the effect of APAP on the expression of anti-apoptotic and antioxidative defense genes, and whether aldose reductase over-expressing plasmid capable to protect against APAP-induced oxidative stress and cell death. APAP treatment induced oxidative stress and hepatotoxicity, and significantly increased aldose reductase mRNA and protein expression in mouse hepatocyte (AML-12). Unexpectedly, AML-12 cells over-expressing aldose reductase augmented APAP-induced reduction in cell viability, reactive oxygen species (ROS) production, glutathione (GSH) depletion and glutathione S-transferase A2 expression. Moreover, over-expression of aldose reductase potentiated APAP induced reduction on proliferating cell nuclear antigen, B cell lymphoma-extra large (bcl-xL), catalase, glutathione peroxidase-1 (GPx-1) and abolished APAP-induced B-cell lymphoma 2 (bcl-2) inductions. Further, over-expression of aldose reductase significantly abolished AMP activated protein kinase (AMPK) activity in APAP-treated cells and induced p53 expression. This results demonstrate that APAP induced toxicity in AML-12, increased aldose reductase expression, and over-expression of aldose reductase render this cell more susceptible to APAP induced oxidative stress and cell death, this probably due to inhibition AMPK or bcl-2 activity, or may due to competition between aldose reductase and glutathione reductase for NADPH.
authors.affiliation: Ministry of Education Key Laboratory for Cell Biology and Tumor Cell Engineering, Department of Biomedical Sciences, School of Life Sciences, Xiamen University, Xiamen, 361005 China ; Department of Biochemistry, Faculty of Medicine, Gadarif University, 32211 Gadarif, Sudan.
authors.forename: Munzir M E
authors.initials: MM
authors.lastname: Ahmed
authors.affiliation: Department of Pathology, Al-Yarmouk College, 11111 Khartoum, Sudan.
authors.forename: J A S
authors.initials: JA
authors.lastname: Al-Obosi
authors.affiliation: Department of Biochemistry, Faculty of Pharmacy, University of National Ribat, Khartoum, Sudan.
authors.forename: H M
authors.initials: HM
authors.lastname: Osman
authors.affiliation: Department of Pharmaceutics, Faculty of Pharmacy, University of Khartoum, Khartoum, Sudan.
authors.forename: M E
authors.initials: ME
authors.lastname: Shayoub
keywords: AML-12; APAP; Acetaminophen; Aldose reductase; Oxidative stress; ROS