Does the [3H]mepyramine binding site represent the histamine H1 receptor? Re-examination of the histamine H1 receptor with quinine.

Mepyramine is a potent H1 receptor antagonist, and [3H]mepyramine generally is used to label histamine H1 receptors. However, we found that [3H]mepyramine labeled not only the H1 receptor but also a [3H]mepyramine binding protein (MBP) in the liver, which protein appears to be related to the subfamily of debrisoquine 4-hydroxylase (cytochrome P450IID) isozymes. The binding of [3H]mepyramine to the cloned H1 receptor was not affected by 1 microM quinine, an inhibitor of debrisoquine 4-hydroxylase. On the other hand, the binding to MBP in the liver membranes was completely inhibited by 1 microM quinine. These data indicate that the labeling by [3H]mepyramine of H1 receptors and MBP can be completely separated with 1 microM quinine. The majority of [3H] mepyramine binding sites in the cerebral cortex, thalamus and hypothalamus, hippocampus, heart, aorta, lung and spleen were H1 receptors. On the other hand, almost all [3H]mepyramine binding sites in the liver and kidney were MBP. Both H1 receptors and MBP were expressed in the stomach, ileum, cerebellum and adrenal gland. Kd values of [3H]mepyramine for membranes from the cerebellum and stomach in the presence of quinine, which tissues contain both H1 receptors and MBP, approached that value of the cloned H1 receptor. The improved [3H]mepyramine binding assay using quinine is a precise method to characterize H1 receptors by the separate determination of H1 receptors and MBP.