SKF 525-A and cytochrome P-450 ligands inhibit with high affinity the binding of [3H]dextromethorphan and sigma ligands to guinea pig brain

• Published in: Life sciences (1973) Vol. 48; no. 6; p. 543
• Main Authors: Klein, M, Canoll, P D, Musacchio, J M
• Format: Journal Article
• Language: English
• Published: Netherlands 1991
• Subjects: Animals; Binding, Competitive; Brain - metabolism; Cytochrome P-450 CYP2D6; Cytochrome P-450 Enzyme System - metabolism; Debrisoquin - pharmacology; Dextromethorphan - metabolism; Guinea Pigs; Kinetics; Ligands; Lobeline - pharmacology; Mixed Function Oxygenases - metabolism; Neurotransmitter Uptake Inhibitors - pharmacology; Piperazines - pharmacology; Proadifen - pharmacology; Receptors, Opioid - drug effects; Receptors, Opioid - metabolism; Receptors, sigma; Sparteine - pharmacology
• ISSN: 0024-3205
• DOI: 10.1016/0024-3205(91)90469-R

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.