DOI: 10.5176/2345-783X_PHARMA15.43
Authors: Rachel F. Tyndale and Kristine L.P. Garcia
Abstract:
For decades the presence of cytochrome P450 enzymes (CYPs) within the brain has been recognized, but their ability to function and potential role in drug response has been unclear. Initially we demonstrated, using mechanism based, suicide substrates (which bind selectively and irreversibly to a specific active enzyme) that CYPs in the brain had sufficient cofactors and coenzymes to be catalytically active in vivo in the rat. Subsequently we have sought to determine circumstances under which the enzymes within the brain are in a position to alter drug response, in the presence of a fully functioning hepatic CYP system. We have recently shown that drug metabolizing enzyme activity, examined using members of the CYP2 subfamily, within the brain can affect drug and toxin metabolic profiles within the brain and their resulting response. Drug metabolism within the brain, for example, can contribute to metabolic activation or inactivation of therapeutic drugs, as well as the metabolic elimination of potential neurotoxins in the brain. CYP2B and CYP2D are high affinity low capacity drug metabolizing enzymes which are expressed in the liver, but have also been characterized in the brains of mice, rats, monkeys and humans. Both enzymes are genetically polymorphic in humans, resulting is a very wide range of enzymatic activity; this is also reflected in a wide range of protein levels within human brain autopsy tissues. In addition, both enzymes are elevated in the brains of human smokers, and induced centrally (and not hepatically) but nicotine treatment in rats and monkeys. We have modeled in rats the variation in human brain CYP2B6 and CYP2D6 activity, using a combination of brain-specific inhibition or induction. We have demonstrated that inhibiting CNS-metabolism increased the levels drug levels, and resulting response, of drugs metabolically inactivated (i.e. Propofol, Nicotine), while decreasing metabolite levels and response for drugs activated by metabolism (i.e. Codeine). Likewise the neurotoxicity resulting from neurotoxins activated (i.e. Chlorpyrifos) or inactivated (i.e MPTP) by CYPs in the brain, can be altered by inhibiting or inducing these enzymes. Taken together, the research summarized herein indicates an that when plasma levels don’t predict drug response, centrally mediated metabolism may be contributing; it also suggests that selective induction or inhibition of brain CYP-mediated metabolism can alter drug/toxin response and may constitute a novel drug development target.
Keywords: CYP, cytochrome P450; CNS, central nervous system; ICV, intracerebroventricular; MBI, mechanism-based inhibitor; MPP+, 1-methyl-4-phenylpyridinium
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