1. Human CYP2D6 is present in brain, metabolizes many drugs and has been im
plicated in Parkinson's and Alzheimer's diseases and some cancers. It is st
ill unclear which of the six known rat CYP2D subfamily members is/are homol
ogous to human CYP2D6.
2. In this study, RT-PCR, Southern and Western blotting and immunohistochem
ical techniques were used to study the distribution of CYP2D subfamily memb
er mRNA and proteins across 10 rat brain regions. CYP2D subfamily mRNA and
protein levels were correlated with brain dextromethorphan O-demethylation
(DOD), a measure of human CYP2D6 and rat CYP2D1 activities.
3. The data showed a strong relationship between CYP2D1 and CYP2D1-18 with
brain DOD activity. In addition, it was shown that CYP2D proteins are prese
nt in brain mitochondrial as well as microsomal membranes. CYP2D subfamily
member mRNA and proteins varied across brain regions and were highly concen
trated in specific cell types.
4. These data strongly suggest that CYP2D1 and not CYP2D5 mediates DOD acti
vity in rat brain, and may be the rat homologue of human CYP2D6. The highly
localized nature of CYP2D indicates that in specific neurones enzyme level
s may approach hepatic levels and, hence, contribute to local alterations i
n brain drug metabolism.