The Use of Ligand Binding Techniques to Identify Transport Proteins: The Characterization of the [125I]-Iodophenylarsine Oxide Receptor in Rat Mitochondrial Membranes

McEnery, Maureen W.; Hoffman, Robert D.

doi:10.1007/978-3-642-78936-6_8

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“…[ 3 H]‐trimetazidine displacement experiments with drugs belonging to various pharmacological classes were performed to characterize the liver mitochondrial binding sites. Potential inhibitors were selected for their known ability to modify transporter activities and ionic fluxes across the mitochondrial membranes and/or to interact with known mitochondrial sites (McEnery & Hoffman, 1994).…”

Section: Resultsmentioning

confidence: 99%

Evidence for the existence of [³H]‐trimetazidine binding sites involved in the regulation of the mitochondrial permeability transition pore

Morin

Elimadi

Sapena

et al. 1998

British J Pharmacology

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Trimetazidine is an anti‐ischaemic drug effective in different experimental models but its mechanism of action is not fully understood. Data indicate that mitochondria could be the main target of this drug. The aim of this work was to investigate the binding of [3H]‐trimetazidine on a purified preparation of rat liver mitochondria. [3H]‐trimetazidine binds to two populations of mitochondrial binding sites with Kd values of 0.96 and 84 μm. The total concentration of binding sites is 113 pmol mg−1 protein. Trimetazidine binding sites are differently distributed. The high‐affinity ones are located on the outer membranes and represent only a small part (4%) of total binding sites, whereas the low‐affinity ones are located on the inner membranes and are more abundant (96%) with a Bmax=108 pmol mg−1 protein. Drug displacement studies with pharmacological markers for different mitochondrial targets showed that [3H]‐trimetazidine binding sites are different from previously described mitochondrial sites. The possible involvement of [3H]‐trimetazidine binding sites in the regulation of the mitochondrial permeability transition pore (MTP), a voltage‐dependent channel sensitive to cyclosporin A, was investigated with mitochondrial swelling experiments. Trimetazidine inhibited the mitochondrial swelling induced by Ca2+ plus tert‐butylhydroperoxide (t‐BH). This effect was concentration‐dependent with an IC50 value of 200 μm. Assuming that trimetazidine effectiveness may be related to its structure as an amphiphilic cation, we compared it with other compounds exhibiting the same chemical characteristic both for their ability to inhibit MTP opening and to displace [3H]‐trimetazidine bound to mitochondria. Selected compounds were drugs known to interact with various biological membranes. A strong correlation between swelling inhibition potency and low‐affinity [3H]‐trimetazidine binding sites was observed: r=0.907 (n=24; P<0.001). These data suggest that mitochondrial sites labelled with [3H]‐trimetazidine may be involved in the MTP inhibiton. British Journal of Pharmacology (1998) 123, 1385–1394; doi:

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Section: Resultsmentioning

confidence: 99%

Evidence for the existence of [³H]‐trimetazidine binding sites involved in the regulation of the mitochondrial permeability transition pore

Morin

Elimadi

Sapena

et al. 1998

British J Pharmacology

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The Use of Ligand Binding Techniques to Identify Transport Proteins: The Characterization of the [125I]-Iodophenylarsine Oxide Receptor in Rat Mitochondrial Membranes

Cited by 1 publication

References 46 publications

Evidence for the existence of [³H]‐trimetazidine binding sites involved in the regulation of the mitochondrial permeability transition pore

Evidence for the existence of [³H]‐trimetazidine binding sites involved in the regulation of the mitochondrial permeability transition pore

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The Use of Ligand Binding Techniques to Identify Transport Proteins: The Characterization of the [125I]-Iodophenylarsine Oxide Receptor in Rat Mitochondrial Membranes

Cited by 1 publication

References 46 publications

Evidence for the existence of [3H]‐trimetazidine binding sites involved in the regulation of the mitochondrial permeability transition pore

Evidence for the existence of [3H]‐trimetazidine binding sites involved in the regulation of the mitochondrial permeability transition pore

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Evidence for the existence of [³H]‐trimetazidine binding sites involved in the regulation of the mitochondrial permeability transition pore

Evidence for the existence of [³H]‐trimetazidine binding sites involved in the regulation of the mitochondrial permeability transition pore