ABSTRACT
Cytochrome P450 is the collective term for a large superfamily of heme-containing proteins that play an important role in the oxidative metabolism of numerous endogenous and foreign compounds.1 The CYP families 1 to 4 are involved in drug metabolism and are preferentially expressed in the liver. Drug metabolizing CYP isoforms also occur in brain and include CYP2B1, CYP2C29, CYP2D4, CYP2E1, CYP4F, CYP3A9, CYP3A11, and CYP3A13.2,3 The CYP isoforms in brain are localized in defined neuronal or glial cell populations.4,5 Several of the CYPs expressed in the brain are inducible by alcohol, neuroleptics, anticonvulsants, and endocrine factors.6-8
Important questions regarding CYPs expressed in brain are whether these enzymes are active in drug and xenobiotic metabolism.9 Pharmaceuticals used in treatment of neurological and mental diseases (e.g., haloperidol, diazepam, carbamazepine, phenytoin) exert their function in specific brain regions, and their local concentration may depend on their biotransformation via internal brain CYP pathways.4,10,11 A characteristic issue of all of these compounds is that they cross the
blood-brain and blood-cerebrospinal fluid barrier mainly by diffusion and therefore penetrate into CYP containing astrocytes, which are a major part of these permeability barriers.12,13
The function of such CYP containing astrocytes in response to xenobiotic exposure is a topic of great interest. Pharmaceuticals like those previously mentioned are potentially effective in specified neurons. Therefore their entrance into brain needs to be effectively controlled. Astrocytes present at the brain border lines might regulate drug influx by CYP dependent biotransformation and therefore balance neuronal exposition to the respective drugs. Astrocytes have intermediary and regulative functions especially in the control of neuronal outgrowth and neuronal immune functions.14-16 The regulation of drug or xenobiotic availability for the neurons may be an important part of these intermediary functions.
