title: Non-cytotoxic concentrations of acetaminophen induced mitochondrial biogenesis and antioxidant response in HepG2 cells.
abstract: Mitochondrial dysfunction has been implicated in acute, severe liver injury caused by overdose of acetaminophen (APAP). However, whether mitochondrial biogenesis is involved is unclear. Here we demonstrated that mitochondrial biogenesis, as indicated by the amounts of mitochondrial DNA and proteins, increased significantly in HepG2 cells exposed to low, non-cytotoxic concentrations of APAP. This heightened response was accompanied by upregulated expression of PGC-1α, NRF-1 and TFAM, which are key transcriptional regulators of mitochondrial biogenesis. Additionally, antioxidants including glutathione, MnSOD, HO-1, NQO1, and Nrf2 were also significantly upregulated. In contrast, for HepG2 cells exposed to high, cytotoxic concentration of APAP, mitochondrial biogenesis was inhibited and the expression of its regulatory proteins and antioxidants were concentration-dependently downregulated. In summary, our study indicated that mitochondrial biogenesis, along with antioxidant induction, may be an important cellular adaptive mechanism counteracting APAP-induced toxicity and overwhelming this cytoprotective capacity could result in liver injury.
authors.affiliation: Evaluation and Research Centre for Toxicology, Institute of Disease Control and Prevention, The Academy of Military Medical Sciences, Beijing, PR China.
authors.forename: Tingfen
authors.initials: T
authors.lastname: Zhang
authors.affiliation: Department of Environmental Health, Rollins School of Public Health, Emory University, Atlanta, GA, USA.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Evaluation and Research Centre for Toxicology, Institute of Disease Control and Prevention, The Academy of Military Medical Sciences, Beijing, PR China.
authors.forename: Jiabin
authors.initials: J
authors.lastname: Guo
authors.affiliation: Evaluation and Research Centre for Toxicology, Institute of Disease Control and Prevention, The Academy of Military Medical Sciences, Beijing, PR China.
authors.forename: Haitao
authors.initials: H
authors.lastname: Yuan
authors.affiliation: Evaluation and Research Centre for Toxicology, Institute of Disease Control and Prevention, The Academy of Military Medical Sciences, Beijing, PR China.
authors.forename: Hui
authors.initials: H
authors.lastname: Peng
authors.affiliation: Evaluation and Research Centre for Toxicology, Institute of Disease Control and Prevention, The Academy of Military Medical Sciences, Beijing, PR China.
authors.forename: Lan
authors.initials: L
authors.lastname: Cui
authors.affiliation: Evaluation and Research Centre for Toxicology, Institute of Disease Control and Prevention, The Academy of Military Medical Sciences, Beijing, PR China.
authors.forename: Jian
authors.initials: J
authors.lastname: Yin
authors.affiliation: Evaluation and Research Centre for Toxicology, Institute of Disease Control and Prevention, The Academy of Military Medical Sciences, Beijing, PR China.
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Evaluation and Research Centre for Toxicology, Institute of Disease Control and Prevention, The Academy of Military Medical Sciences, Beijing, PR China.
authors.forename: Jun
authors.initials: J
authors.lastname: Zhao
authors.affiliation: Unilever Safety and Environmental Assurance Center, Colworth Science Park, Sharnbrook, Bedfordshire MK44 1LQ, UK.
authors.forename: Jin
authors.initials: J
authors.lastname: Li
authors.affiliation: Unilever Safety and Environmental Assurance Center, Colworth Science Park, Sharnbrook, Bedfordshire MK44 1LQ, UK.
authors.forename: Andrew
authors.initials: A
authors.lastname: White
authors.affiliation: Unilever Safety and Environmental Assurance Center, Colworth Science Park, Sharnbrook, Bedfordshire MK44 1LQ, UK.
authors.forename: Paul L
authors.initials: PL
authors.lastname: Carmichael
authors.affiliation: Unilever Safety and Environmental Assurance Center, Colworth Science Park, Sharnbrook, Bedfordshire MK44 1LQ, UK.
authors.forename: Carl
authors.initials: C
authors.lastname: Westmoreland
authors.affiliation: Evaluation and Research Centre for Toxicology, Institute of Disease Control and Prevention, The Academy of Military Medical Sciences, Beijing, PR China. Electronic address: pengsq@hotmail.com.
authors.forename: Shuangqing
authors.initials: S
authors.lastname: Peng
mesh_terms: D000082:Acetaminophen / Q000008:administration & dosage / Q000009:adverse effects*; D000975:Antioxidants / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects; D005978:Glutathione / Q000378:metabolism; D056945:Hep G2 Cells / Q000187:drug effects; D006801:Humans; D008099:Liver / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000235:genetics; D051266:Nuclear Respiratory Factor 1 / Q000235:genetics; D001678:Organelle Biogenesis; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / Q000235:genetics; D013481:Superoxides / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000975:Antioxidants; D004268:DNA-Binding Proteins; D024101:Mitochondrial Proteins; C495633:NRF1 protein, human; D051266:Nuclear Respiratory Factor 1; C486497:PPARGC1A protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C499631:TFAM protein, human; D014157:Transcription Factors; D013481:Superoxides; D000082:Acetaminophen; D005978:Glutathione
keywords: Acetaminophen; Hepatotoxicity; Mitochondrial biogenesis; Nrf2; PGC-1α; Risk assessment