STRAIN DIFFERENCES IN RAT-BRAIN AND LIVER SIGMA-BINDING - LACK OF CYTOCHROME-P-450-2D1 INVOLVEMENT

Substrates for cytochrome P450-2D1 exhibit a high affinity for sigma binding sites suggesting that sigma 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 sigma sites is associated with the P450-2D1 enzyme, then the number (B(max)) of sigma sites is predicted to be decreased in Dark Agouti brain and liver compared to Sprague-Dawley tissues. In the present study, binding of [H-3](+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine ([H-3](+)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 sigma 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 sigma binding; but rather, other genetic factor(s) may be responsible for the decrease in the number of sigma sites in the Dark Agouti strain compared to the other rat strains examined.