title: Oxidative Stress Mechanisms Do Not Discriminate between Genotoxic and Nongenotoxic Liver Carcinogens.
abstract: It is widely accepted that in chemical carcinogenesis different modes-of-action exist, e.g., genotoxic (GTX) versus nongenotoxic (NGTX) carcinogenesis. In this context, it has been suggested that oxidative stress response pathways are typical for NGTX carcinogenesis. To evaluate this, we examined oxidative stress-related changes in gene expression, cell cycle distribution, and (oxidative) DNA damage in human hepatoma cells (HepG2) exposed to GTX-, NGTX-, and noncarcinogens, at multiple time points (4-8-24-48-72 h). Two GTX (azathriopine (AZA) and furan) and two NGTX (tetradecanoyl-phorbol-acetate, (TPA) and tetrachloroethylene (TCE)) carcinogens as well as two noncarcinogens (diazinon (DZN, d-mannitol (Dman)) were selected, while per class one compound was deemed to induce oxidative stress and the other not. Oxidative stressors AZA, TPA, and DZN induced a 10-fold higher number of gene expression changes over time compared to those of furan, TCE, or Dman treatment. Genes commonly expressed among AZA, TPA, and DZN were specifically involved in oxidative stress, DNA damage, and immune responses. However, differences in gene expression between GTX and NGTX carcinogens did not correlate to oxidative stress or DNA damage but could instead be assigned to compound-specific characteristics. This conclusion was underlined by results from functional readouts on ROS formation and (oxidative) DNA damage. Therefore, oxidative stress may represent the underlying cause for increased risk of liver toxicity and even carcinogenesis; however, it does not discriminate between GTX and NGTX carcinogens.
authors.affiliation: Department of Toxicogenomics, School of Oncology and Developmental Biology (GROW), Maastricht University, 6200 MD Maastricht, The Netherlands.
authors.forename: Lize
authors.initials: L
authors.lastname: Deferme
authors.affiliation: Department of Toxicogenomics, School of Oncology and Developmental Biology (GROW), Maastricht University, 6200 MD Maastricht, The Netherlands.
authors.forename: Jarno
authors.initials: J
authors.lastname: Wolters
authors.affiliation: Department of Toxicogenomics, School of Oncology and Developmental Biology (GROW), Maastricht University, 6200 MD Maastricht, The Netherlands.
authors.forename: Sandra
authors.initials: S
authors.lastname: Claessen
authors.affiliation: Department of Toxicogenomics, School of Oncology and Developmental Biology (GROW), Maastricht University, 6200 MD Maastricht, The Netherlands.
authors.forename: Jacco
authors.initials: J
authors.lastname: Briedé
authors.affiliation: Department of Toxicogenomics, School of Oncology and Developmental Biology (GROW), Maastricht University, 6200 MD Maastricht, The Netherlands.
authors.forename: Jos
authors.initials: J
authors.lastname: Kleinjans
mesh_terms: D002273:Carcinogens / Q000145:classification* / Q000633:toxicity; D004249:DNA Damage; D056945:Hep G2 Cells; D006801:Humans; D008099:Liver / Q000473:pathology*; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000032:analysis; D013997:Time Factors
chemical_list: D002273:Carcinogens; D017382:Reactive Oxygen Species