Catecholamine depletion and accumulation of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and 1-methyl-4-phenylpyridinium (MPP(+)) in adrenal medullary chromaffin cells.
Cultures of bovine adrenal medullary chromaffin cells converted 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to 1-methyl-4-phenylpyridinium (MPP(+)) by a pargyline-sensitive mechanism. Both MPTP and MPP(+) accumulated in these cells. Upon subcellular fractionation, distribution of MPP(+) paralleled that of catecholamines, suggesting storage in chromaffin vesicles. In contrast, MPTP was found in both soluble and particulate fractions, but not in chromaffin vesicles. MPTP produced a rapid depletion of 20-25% of chromaffin cell catecholamines, an action blocked by the nicotinic antagonist d-tubocurarine but not by the monoamine oxidase inhibitor pargyline. This depletion was not mimicked by MPP(+). Addition of > OR = 50 microM MPTP to chromaffin cell cultures caused additional, progressive catecholamine loss from 1 to 6 days of drug exposure that was mimicked by MPP(+) and not blocked by pargyline or d-tubocurarine. Cultures of bovine adrenal cortical cells also converted MPTP to MPP(+) and accumulated both of these drugs, but at a slower rate and to a lesser extent than chromaffin cells. Although chromaffin cells form MPP(+) from MPTP and store MPP(+), these studies suggest that catecholamine depletion in these cells results from the actions of MPTP and MPP(+) which are not stored in chromaffin vesicles. MPTP evokes catecholamine secretion from chromaffin cells via nicotinic acetylcholine receptors. MPTP and free MPP(+) are also toxic to the cells, probably through blockade of metabolic processes. These findings suggest that cells with a high capacity for MPP(+) uptake but limited vesicular storage capacity, i.e. sustained high cytoplasmic drug levels, would be susceptible to the toxic actions of this drug.
Wilson
S P
SP
Department of Pharmacology, University of South Carolina School of Medicine, Columbia, SC 29208, USA.
Beeler
J F
JF