Brain Drug-Metabolizing Cytochrome P450 Enzymes are Active In Vivo, Demonstrated by Mechanism-Based Enzyme Inhibition

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