The long-term objective is to determine the important biological functions of microsomal cytochrome P450 (P450) enzymes in different parts of the central nervous system. These functions may be targets for chemical toxicity associated with exposure to environmental chemicals, drugs, and therapeutic agents. The current application for a two-year, exploratory/developmental application will focus on the development and initial characterization of a tissue-specific knockout mouse model in which the NADPH-cytochrome P450 reductase (CPR) gene is deleted from neuronal cells throughout the adult brain. The hypothesis is that microsomal P450 enzymes play crucial roles in the brain by maintaining the homeostasis of various endogenous substances, such as sex steroids, flucocorticoids, eicosanoids, and retinoids, which are synthesized locally or absorbed from the circulation, and by metabolic disposition of numerous exogenous compounds. Thus, disruption of the function of these enzymes may lead to disturbance of normal brain function and a decease in the local detoxification capacity.
The Specific Aims are: 1) to generate, through Cre-mediated recombination of the floxed CPR gene, and characterize mice with specific deletion of the CPR gene in the brain; 2) to explore the potential impact of brain-selective deletion of the CPR gene on brain structure and on various aspects of brain function. The effects of tissue-selective CPR-deletion on general health, gross development, and brain structure will be characterized. The potential detrimental consequences on brain function will be explored using several behavioral tests. The results will form the basis for a future RO1 application to identify the mechanistic basis of any abnormal phenotypes observed and to fully characterize this mouse model for studies on P450 function, drug metabolism, and xenobiotic toxicity in the brain.
| Fang, C; Bolivar, V J; Gu, J et al. (2012) Neurobehavioral abnormalities in a brain-specific NADPH-cytochrome P450 reductase knockout mouse model. Neuroscience 218:170-80 |
