Effect of cytochrome P450 1A induction on oxidative damage in rat brain

Polycyclic and halogenated aromatic hydrocarbons (PAHs and HAHs) can enhanc e the generation of reactive oxygen species (ROS) by inducing cytochrome P4 50 1A (CYP 1A) in vivo and in vitro. While the brain is vulnerable to oxida tive injury, whether or not CYP 1A induction in the brain can produce measu rable levels of oxidative damage has not been reported. The objective of th is study was to investigate the effect of this induction on oxidative damag e to the CNS. Time course changes in rat brain CYP 1A activity were determi ned by measurement of ethoxyresorufin O-deethylase (EROD) activity in whole brain homogenates. Three days after exposure of rats to five daily injecti ons of 3-methylcholanthrene (3-MC) an approximately sevenfold increase in E ROD activity was observed. Hepatic levels were increased 60-100 fold. This increase in CYP 1A activity was not accompanied by increased protein or lip id oxidation as measured by tryptophan fluorescence and TBAR formation, or decreased glutamine synthetase (GS) activity. These findings indicate that if increased CYP 1A activity in the brain following 3-MC treatment leads to increased ROS generation, the increase is insufficient to overwhelm the en dogenous antioxidant defense system, produce detectable oxidative damage, a nd alter glutamate homeostasis.