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 b inding sites suggesting that sigma sites may be associated with the cy tochrome 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, t hen the number (B(max)) of sigma sites is predicted to be decreased in Dark Agouti brain and liver compared to Sprague-Dawley tissues. In th e present study, binding of H-3](+)-3-(3-hydroxyphenyl)-N-(1-propyl)pi peridine ([H-3](+)3-PPP) in brain and liver from Dark Agouti, Sprague- Dawley, Long Evans and Wistar rat strains was examined. Results demons trate marked variation in B(max) among the strains, with a consistentl y lower value for Dark Agouti tissues. However, the absolute differenc e in sigma binding between brain and liver for each strain was not con sistent with reported differences in the activity or levels of P450-2D 1. Additionally, the percentage decrease in B(max) for Dark Agouti liv er was found to be similar to that for Dark Agouti brain. Taken togeth er 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 i n the Dark Agouti strain compared to the other rat strains examined.