SKF 525-A and cytochrome P-450 ligands inhibit with high affinity the binding of [3H]dextromethorphan and sigma ligands to guinea pig brain.
The DM1/sigma 1 site binds dextromethorphan (DM) and sigma receptor ligands. The broad binding specificity of this site and its peculiar subcellular distribution prompted us to explore the possibility that this site is a member of the cytochrome P-450 superfamily of enzymes. We tested the effects of the liver microsomal monooxygenase inhibitor SKF 525-A (Proadifen), and other P-450 substrates on the binding of [3H]dextromethorphan, [3H]3-(-3-Hydroxyphenyl)-N-(1-propyl)piperidine and (+)-[3H]1,3-Di-o-tolyl-guanidine ([3H]DTG) to the guinea pig brain. SKF 525-A, l-lobeline and GBR-12909 inhibited the binding of the three labeled ligands with nM affinity. Each drug has identical nM Ki values for the high-affinity site labeled by the three ligands. This indicated that they displaced the labeled ligands from the common DM1/sigma 1 site. Debrisoquine and sparteine, prototypical substrates for liver debrisoquine 4-hydroxylase, displayed Ki values of 9-13 and 3-4 microM respectively against the three labeled ligands. These results, the broad specificity of the DM1/sigma 1 binding site, and its peculiar subcellular distribution, raises the possibility that this binding site is a member of the cytochrome P-450 superfamily of isozymes, rather than a neurotransmitter receptor. These findings may have important implications for the understanding of the therapeutic, side effects and toxicity of several neurotropic drugs.
Klein
M
M
Department of Pharmacology, N.Y.U. Medical Center, NY 10016.
Canoll
P D
PD
Musacchio
J M
JM
D000818:Animals; D001667:Binding, Competitive; D001921:Brain / Q000378:metabolism*; D019389:Cytochrome P-450 CYP2D6; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D003647:Debrisoquin / Q000494:pharmacology*; D003915:Dextromethorphan / Q000378:metabolism*; D006168:Guinea Pigs; D007700:Kinetics; D008024:Ligands; D008120:Lobeline / Q000494:pharmacology*; D006899:Mixed Function Oxygenases / Q000378:metabolism; D014179:Neurotransmitter Uptake Inhibitors / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology*; D011335:Proadifen / Q000494:pharmacology*; D011957:Receptors, Opioid / Q000187:drug effects / Q000378:metabolism*; D017480:Receptors, sigma; D013034:Sparteine / Q000494:pharmacology
D008024:Ligands; D014179:Neurotransmitter Uptake Inhibitors; D010879:Piperazines; D011957:Receptors, Opioid; D017480:Receptors, sigma; D013034:Sparteine; D003915:Dextromethorphan; D003577:Cytochrome P-450 Enzyme System; C043425:vanoxerine; D011335:Proadifen; D008120:Lobeline; D006899:Mixed Function Oxygenases; D019389:Cytochrome P-450 CYP2D6; D003647:Debrisoquin