Cytochrome P450 enzymes and metabolism of drugs and neurotoxins within the mammalian brain.

Cytochrome P450 enzymes (CYPs) that metabolize xenobiotics are expressed and active in the brain. These CYPs contribute to the metabolism of many centrally acting compounds, including clinically used drugs, drugs of abuse, and neurotoxins. Although CYP levels are lower in the brain than in the liver, they may influence central substrate and metabolite concentrations, which could alter resulting centrally-mediated responses to these compounds. Additionally, xenobiotic metabolizing CYPs are highly variable due to genetic polymorphisms and regulation by endogenous and xenobiotic molecules. In the brain, these CYPs are sensitive to xenobiotic induction. As a result, CYPs in the brain vary widely, including among humans, and this CYP variation may influence central metabolism and resulting response to centrally acting compounds. It has been demonstrated, using experimental manipulation of CYP activity in vivo selectively within the brain, that CYP metabolism in the brain alters central substrate and metabolite concentrations, as well as drug response and neurotoxic effects. This suggests that variability in xenobiotic metabolizing CYPs in the human brain may meaningfully contribute to individual differences in response to, and effects of, centrally acting drugs and neurotoxins. This chapter will provide an overview of CYP expression in the brain, endogenous- and xenobiotic-mediated CYP regulation, and the functional impact of CYP-mediated metabolism of drugs and neurotoxins in the brain, with a focus on experimental approaches in mice, rats, and non-human primates, and a discussion regarding the potential role of xenobiotic metabolizing CYPs in the human brain.