Uptake, release, and subcellular localization of 1-methyl-4-phenylpyridinium in blood platelets.
The neurotoxic compound 1-[methyl-3H]-4-phenylpyridinium ([3H]MPP+) was actively taken up by human, rabbit, and guinea pig platelets incubated in plasma. In human platelets, the apparent Km of this uptake (22.6 microM) was 50 times higher than that for serotonin [5-hydroxytryptamine (5-HT]). The uptake of [3H]MPP+ by human platelets was inhibited by selective 5-HT uptake blockers [cianopramine, (-)-paroxetine, and clomipramine], by metabolic inhibitors (KCN and ouabain), and by drugs that interfere with amine storage in the 5-HT organelles (reserpine, mepacrine, and Ro 4-1284). Impairment of the transmembrane proton gradient by ionophores (monensin and nigericin) induced a marked release of radioactivity from platelets preincubated with [3H]MPP+. Fractionation of homogenates of rabbit platelets preincubated with [3H]MPP+ showed that the drug was concentrated to a great extent in the 5-HT organelle fraction. MPP+ competitively inhibited [14C]5-HT uptake by human platelets and reduced the endogenous 5-HT content of human, rabbit, and guinea pig platelets. These investigations show that MPP+ is transported into the platelets via the 5-HT carrier and is accumulated predominantly in the subcellular organelles that store 5-HT and other monoamines. It is suggested that an accumulation of MPP+ in amine storage vesicles of neurons may be involved in the effects of the drug in the CNS, e.g., by protecting other subcellular compartments from exposure to high concentrations of MPP+, by sustaining a gradual release of the toxin, or both.
D015655:1-Methyl-4-phenylpyridinium; D000818:Animals; D001792:Blood Platelets / Q000378:metabolism*; D006168:Guinea Pigs; D006801:Humans; D011726:Pyridinium Compounds / Q000032:analysis / Q000378:metabolism*; D011817:Rabbits; D051381:Rats; D012701:Serotonin / Q000378:metabolism; D013347:Subcellular Fractions / Q000032:analysis; D013574:Synaptosomes / Q000378:metabolism
D011726:Pyridinium Compounds; D012701:Serotonin; D015655:1-Methyl-4-phenylpyridinium