1. ¹Centre for Addiction and Mental Health, University of Toronto, Toronto, ON, Canada
2. ²Department of Pharmacology, University of Toronto, Toronto, ON, Canada

Correspondence: Dr S Miksys, Department of Pharmacology, Rm 4334, University of Toronto, 1 King's College Circle, Toronto, ON, Canada M5S 1A8. Tel: +416 978 5155; Fax: +416 978 6395; E-mail: s.miksys@utoronto.ca

Received 25 April 2008; Revised 28 June 2008; Accepted 29 June 2008; Published online 30 July 2008.

Abstract

Individuals vary in their response to centrally acting drugs, and this is not always predicted by drug plasma levels. Central metabolism by brain cytochromes P450 (CYPs) may contribute to interindividual variation in response to drugs. Brain CYPs have unique regional and cell-type expression and induction patterns, and they are regulated independently of their hepatic isoforms. In vitro, these enzymes can metabolize endogenous and xenobiotic substrates including centrally acting drugs, but there is no evidence to date of their in vivo function. This has been difficult to demonstrate in the presence of hepatically derived metabolites that may cross the blood–brain barrier. In addition, because of the membrane location of brain CYPs and the rate limiting effect of endogenous heme levels on the activity and appropriate membrane insertion of some induced CYPs, it has been unclear whether sufficient cofactors and coenzymes are present for constitutive and induced CYP forms to be enzymatically active. We have developed a method using a radiolabeled mechanism-based inhibitor of CYP2B1, ³H-8-methoxypsoralen, to demonstrate for the first time that both the constitutive and induced forms of this enzyme are active in situ in the living rat brain. This methodology provides a novel approach to assess the function of enzymes in extrahepatic tissues, where expression levels are often low. Selective induction of metabolically active drug metabolizing enzymes in the brain may also provide ways to control prodrug activation in specific brain regions as a novel therapeutic avenue.