Inhibition of catecholamine transport into chromaffin granule ghosts isolated from bovine adrenal glands by phenytoin.
The anticonvulsant drug, phenytoin, has been reported to inhibit both the transport of catecholamines into synaptosomes and monoamine oxidase. The objective of this research was to determine whether phenytoin inhibited the transport of catecholamines into storage granules. This was tested by examining the effects of phenytoin (0.05 to 0.4 mM) on the ability of (-)-[3H] norepinephrine to be transported into chromaffin granule "ghosts" isolated from bovine adrenal glands. Our results indicated that phenytoin, but not phenobarbital, inhibited catecholamine transport in a dose-dependent manner with 50% inhibition occurring at a phenytoin concentration of 0.2 mM. Kinetic analysis of the effects of phenytoin on this transport process indicated that phenytoin was a competitive inhibitor of catecholamine transport with an approximate Ki of 0.3 mM. Furthermore, phenytoin did not inhibit the Mg adenosine triphosphatase required for providing the energy source for the catecholamine transport process, nor did it dissipate the membrane potential generated by this enzyme. The competitive inhibition of catecholamine transport produced by phenytoin is probably not related to the anticonvulsant effects of the drug as it occurred at greater than therapeutic concentrations. However, this effect may be related to the toxic effect of the drug.
D000251:Adenosine Triphosphatases / Q000378:metabolism; D000311:Adrenal Glands / Q000166:cytology*; D000818:Animals; D001693:Biological Transport, Active / Q000187:drug effects; D017301:Ca(2+) Mg(2+)-ATPase; D002395:Catecholamines / Q000378:metabolism*; D002417:Cattle; D002837:Chromaffin Granules / Q000378:metabolism*; D002838:Chromaffin System / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D007700:Kinetics; D008564:Membrane Potentials / Q000187:drug effects; D009638:Norepinephrine / Q000378:metabolism; D010634:Phenobarbital / Q000494:pharmacology; D010672:Phenytoin / Q000494:pharmacology*
D002395:Catecholamines; D010672:Phenytoin; D000251:Adenosine Triphosphatases; D017301:Ca(2+) Mg(2+)-ATPase; D009638:Norepinephrine; D010634:Phenobarbital