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Mechanism of interaction of ticlopidine and its analogues with the energy-conserving mechanism in mitochondria.

Abstract：

:It was shown recently that the antiaggregating agent ticlopidine and some of its analogues inhibit the energy-conserving mechanism in mitochondria [Abou-Khalil et al., Biochem. Pharmac. 33, 3893 (1984)]. In the present investigation, the mechanism of inhibition by these drugs was investigated by studying their effects on key reactions of oxidative phosphorylation. Liver mitochondria were isolated from Sprague-Dawley male rats, and the interactions of ticlopidine and six of its analogues with those key reactions were tested. We found: The transport of phosphate, glutamate and succinate into mitochondria was not affected significantly by ticlopidine or any of its analogues; however, it was inhibited by both mersalyl and N-ethylmaleimide as expected. There was no inhibitory effect of the tested drugs on the mitochondrial [3H]ADP translocation activity; rather, ticlopidine produced a concentration-dependent increase of that activity, reaching 54% with 20 micrograms/ml. Ticlopidine and its analogue, PCR 5325, increased the latent ATPase activity by about 400% and the DNP-dependent ATPase by about 50%. Also, PCR 4099 caused a 115% increase in the latent activity, whereas the effects of the remaining analogues varied from slight activation to slight inhibition. Under nonphosphorylation conditions, the mitochondrial H+ extrusion resulting from succinate oxidation was inhibited by ticlopidine in a concentration-dependent manner reaching a quasi total inhibition with 40 micrograms/ml. While PCR 5325 gave results similar to ticlopidine, PCR 4099 was less inhibitory and the other analogues were ineffective. These data indicate that the inhibitory action caused by ticlopidine and some of its analogues on oxidative phosphorylation does not reside at one particular site in the mitochondrial membrane; rather, the inhibition seems to be the outcome of profound alterations in mitochondrial ADP translocase, latent ATPase, and proton translocation in the respiratory chain.

journal_name

Biochem Pharmacol

journal_title

Biochemical pharmacology

authors

Abou-Khalil S,Abou-Khalil WH,Yunis AA

doi

10.1016/0006-2952(86)90303-5

subject

Has Abstract

pub_date

1986-06-01 00:00:00

pages

1855-9

issue

11

eissn

0006-2952

issn

1873-2968

pii

0006-2952(86)90303-5

journal_volume

35

pub_type

杂志文章

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