1 research outputs found
Oxidative Stress Mechanisms Do Not Discriminate between Genotoxic and Nongenotoxic Liver Carcinogens
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