Metabolism of xenobiotics in the central nervous system: implications and challenges.

The metabolism of drugs and other xenobiotics in situ in the brain has far-reaching implications in the pharmacological and pharmacodynamic effects of drugs acting on the CNS, particularly with respect to psychoactive drugs wherein a wide range of therapeutic response is typically seen in the patient population. An entirely functional cytochrome P450 (P450) monooxygenase system is known to exist in the rodent and human brain, wherein it is preferentially localized in the neuronal cells, which are the sites of action of psychoactive drugs. Further, bioactivation of xenobiotics, in situ, in the CNS would result in the formation of reactive, toxic metabolites in the neuronal cells that have limited regenerative capability. The presence of P450 enzymes in selective cell populations within distinctive regions of the brain that are affected in certain neurodegenerative disorders implies the potential role of P450-mediated bioactivation as a causative factor in the etiopathogenesis of these diseases. The characterization of brain-specific P450s and their regulation and localization within the CNS assume importance for understanding the potential role of these enzymes in the pathogenesis of neurodegenerative disorders and psychopharmacological modulation of drugs acting on the CNS.