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[3H]GBR-12935 binding to cytochrome P450 in the human brain
P Allard1, J O Marcusson, S B Ross
1Department of Psychiatry, University of Umeå, Sweden.
Journal of Neurochemistry
|January 1, 1994
Summary
This study identifies [3H]GBR-12935 binding sites in the human brain, suggesting a portion represents cytochrome P450IID6, a key enzyme. This finding has implications for understanding the brain
Area of Science:
- Neuropharmacology
- Biochemistry
- Enzymology
Background:
- Multiple [3H]GBR-12935 binding sites exist in the human brain, including dopamine uptake sites.
- In rats, [3H]GBR-12935 binds to nondopaminergic piperazine acceptor sites, identified as cytochrome P450IID1 in dogs.
Purpose of the Study:
- To investigate [3H]GBR-12935 binding to piperazine acceptor sites in the human brain.
- To pharmacologically define these sites and explore their potential identity as cytochrome P450 enzymes.
Main Methods:
- Pharmacological characterization of [3H]GBR-12935 binding using GBR-12909 and mazindol.
- Competition assays with cytochrome P450-sensitive drugs (cis-flupentixol, proadifen/SKF 525 A).
- Examination of binding site distribution across 12 human brain regions.
Main Results:
- A specific binding fraction of [3H]GBR-12935 was pharmacologically defined, exhibiting saturable binding with high affinity (3-8 nM).
- Cytochrome P450-sensitive drugs competed for these sites, supporting their cytochrome P450 nature.
- Findings suggest this fraction represents cytochrome P450IID6, the human ortholog of P450IID1.
- No significant differences in binding densities were observed across the 12 brain regions examined.
Conclusions:
- The study provides a pharmacological definition for piperazine acceptor sites in the human brain.
- Evidence supports the identification of these sites as cytochrome P450IID6.
- The findings highlight the significance of the cytochrome P450 system within the brain.