Effects of ticlopidine, a new platelet antiaggregating agent, and its analogues on mitochondrial metabolism. Oxidative phosphorylation, protein synthesis and DNA polymerase activity.

Abstract:

The effects of ticlopidine and six of its analogues on mitochondrial functions were studied in isolated rat liver mitochondria. The influence of ticlopidine and each of the following analogues: PCR 5325, PCR 4099, PCR 3787, PCR 2362, PCR 4499 and PCR 0665 was evaluated by determining their interaction with three major mitochondrial activities. (A) Oxidative phosphorylation, measured by oxypolarography, was assayed in the presence of glutamate or succinate as source of energy, and both State 4 and State 3 were recorded. Ticlopidine, at 20 micrograms/ml, slightly increased glutamate State 4, whereas it was without effect on that of succinate. At higher concentration (40 micrograms/ml), ticlopidine caused 40-45% inhibition of State 4 with both substrates. All the other analogues tested at either 20 or 40 micrograms/ml were virtually without effect on the respiration. However, at 20 micrograms/ml, ticlopidine and some of its analogues inhibited mitochondrial State 3, while under similar conditions other analogues had little or no effect on this state. (B) Mitochondrial protein synthesis, measured by [14C]-L-leucine incorporation, was not affected significantly by any of these drugs. Whereas chloramphenicol at 10 micrograms/ml caused 80% inhibition, ticlopidine and its analogues in concentrations inhibitory to State 3 did not inhibit mitochondrial protein synthesis. (C) Mitochondrial DNA polymerase activity, determined by [3H] thymidine 5'-triphosphate incorporation, was not inhibited by these drugs. We conclude that, while ticlopidine and analogues have little or no effect on either mitochondrial protein synthesis or mitochondrial DNA polymerase activity, ticlopidine and some of its analogues are inhibitory of the energy conserving mechanism in mitochondria.

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