TY - JOUR T1 - Model Experiments on the Molecular Mechanism of Action of 6-Hydroxydopamine JF - Molecular Pharmacology JO - Mol Pharmacol SP - 147 LP - 154 VL - 7 IS - 2 AU - A. SANER AU - H. THOENEN Y1 - 1971/03/01 UR - http://molpharm.aspetjournals.org/content/7/2/147.abstract N2 - 6-Hydroxydopamine is rapidly oxidized to its p-quinone and indoline derivatives at pH 7.4, as shown by ultraviolet spectroscopy. Incubation of bovine serum albumin (0.5 mM) with 3H-6-hydroxydopamine resulted in covalent binding (nonextractable with alcoholic perchloric acid) of radioactivity to time protein. The amount of radioactivity bound was concentration-dependent. At pH 7.4 and 38°, saturation was reached at a concentration of 70 mM 3H-6-hydroxydopamine. The radioactivity bound at this concentration corresponds to the equivalent of 11 moles of 3H-6-hydroxydopamine per mole of albumin. If oxidation of 3H-6-hydroxydopamine was prevented by Na2S2O5, the binding of radioactivity to bovine albumin was virtually completely abolished. Acetylation of albumin reduced the bound radioactivity to 19% of that of controls, whereas heat denaturation reduced it to only 75%, indicating that not denaturation as such, but the blockade of nucleophilic groups, is the main cause for the reduced binding of radioactivity. The results of the present experiments are compatible with the hypothesis put forward recently [H. Thoenen, J. P. Tranzer and G. Häusler, in "New Aspects of Storage and Release Mechanisms of Catecholamines" (H. J. Schümann and G. Kroneberg, eds.), p. 130. Springer-Verlag, Berlin, 1970] that the selective destruction of adrenergic nerve terminals by 6-hydroxydopamine results from the covalent binding of its oxidation products to nucleophilic groups of biological macromolecules. The reaction seems to be nonspecific, and the high gelectivity of the destructive effect results from the efficient uptake of 6-hydroxydopamine into the adrenergic nerve terminals. ER -