Abstract
Cytochrome P450 (CYP) enzymes play a critical role in the activation and detoxication of many neurotoxic chemicals. While research has largely focused on CYP-mediated metabolism in the liver, emerging evidence suggests that brain CYPs influence neurotoxicity by modulating local metabolite levels. As a first step towards better understanding the relative role of brain CYPs in determining neurotoxic outcome, we characterized mRNA expression of specific CYP isoforms in the rodent brain. Adult mice (male and female) and rats (male) were treated with vehicle, phenobarbital or dexamethasone. Transcripts for CYP2B, CYP3A, CYP1A2 and the orphan CYP4X1 and 2S1 were quantified in the liver, hippocampus, cortex and cerebellum by qPCR. These CYPs were all detected in the liver with the exception of CYP4X1, which was detected in rat but not mouse liver. CYP expression profiles in the brain varied regionally. With the exception of the hippocampus, there were no sex differences in regional brain CYP expression profiles in mice; however, there were marked species differences. In the liver, phenobarbital induced CYP2B expression in both species. Dexamethasone induced hepatic CYP2B and CYP3A in mice but not rats. In contrast, brain CYPs did not respond to these classic hepatic CYP inducers. Our findings demonstrate that CYP mRNA expression in the brain varies by region, that regional brain CYP profiles vary between species and their induction varies from that of hepatic CYPs. These novel data will be useful for designing mechanistic studies to examine the relative role of CYP-mediated brain metabolism in neurotoxicity.
- The American Society for Pharmacology and Experimental Therapeutics