Strain differences in rat brain and liver σ binding: lack of cytochrome P450-2D1 involvement

Substrates for cytochrome P450-2D1 exhibit a high affinity for σ binding sites suggesting that σ sites may be associated with the cytochrome P450-2D1 isozyme. In contrast to Sprague-Dawley, Dark Agouti rat liver does not express the P450-2D1 gene product. Therefore, if a subpopulation of σ sites is associated with the P450-2D1 enzyme, then the number (B_max) of σ sites is predicted to be decreased in Dark Agouti brain and liver compared to Sprague-Dawley tissues. In the present study, binding of [³H](+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine ([³H](+)3-PPP) in brain and liver from Dark Agouti, Sprague-Dawley, Long Evans and Wistar rat strains was examined. Results demonstrate marked variation in B_max among the strains, with a consistently lower value for Dark Agouti tissues. However, the absolute difference in σ binding between brain and liver for each strain was not consistent with reported differences in the activity or levels of P450-2D1. Additionally, the percentage decrease in B_max for Dark Agouti liver was found to be similar to that for Dark Agouti brain. Taken together these results suggest that P450-2D1 does not account for the strain-related difference in σ binding; but rather, other genetic factor(s) may be responsible for the decrease in the number of σ sites in the Dark Agouti strain compared to the other rat strains examined.