A reliable and rapid procedure to estimate drug partitioning in biomembranes

Custódio, José B.A.; Almeida, Leonor M.; Madeira, Vı́tor M.C.

doi:10.1016/0006-291x(91)90394-m

Cited by 66 publications

(80 citation statements)

References 24 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…TAM was added in ethanolic solutions (up to 6 l) to the reaction medium with mitochondria and allowed to incubate for 3 min before starting the reactions. This incubation period was carried out to ensure the complete internalization of the compound on the membrane due to its lipophilic characteristic (Custódio et al, 1991). Care was taken to ensure a final assay volume of 1 ml after the additions.…”

Section: Methodsmentioning

confidence: 99%

“…Moreover, the inhibition of respiration induced by TAM concentrations above 40 M may be partly due to the disruption of the mitochondrial inner membrane and not to an interaction of TAM with the electron transport chain. Furthermore, the decrease in respiration caused by TAM may reflect other membrane-dependent biological activities of this drug, since TAM, with a pKa ϳ8.5, is a protonated quaternary ammonium cation at the used experimental pH that partitions strongly in biomembranes (Custódio et al, 1991) and decreases its fluidity (Custódio et al, 1993). As reported for a few lipophilic compounds possessing base-and acid-dissociative groups, with characteristics and effects very similar to those of TAM and also known as uncouplers [e.g., AU-1421 (Nagamune et al, 1993), phloretin (Jonge et al, 1983), amiodarone (Fromenty et al, 1990), local anesthetics (Garlid and Nakashima, 1983), and several nongenotoxic carcinogens (Keller et al, 1992)], the ionizable group of TAM could change the membrane surface potential, thereby changing the interactions between the components of the respiratory chain.…”

Section: Fig 5 Effects Of Tam (-) Andmentioning

confidence: 99%

“…Therefore, the observed stimulation of state 4 by TAM suggests an increase in the proton leak, pointing out that TAM could act as a proton shuttle or by disrupting the structure of the mitochondrial membrane (Murphy, 1989). The high hydrophobic character and strong partition in biomembranes (Custódio et al, 1991) make it possible for TAM to act as a proton shuttle, since its amine group may bind and translocate protons across the mitochondrial inner membrane. The charged protonated form of tamoxifen may be membrane permeable, thus determining the increase in proton leak induced by this drug and acting like a classic protonophore.…”

mentioning

confidence: 95%

“…Moreover, it has been reported that TAM induces multiple cellular adverse effects, including hemolytic action (Suwalsky et al, 1998;Cruz Silva et al, 2000) and inhibition of mitochondrial permeability transition (Custódio et al, 1998). However, the multiple mechanisms underlying the TAM-induced cytotoxic effects have not been fully understood and the identification of such mechanisms is relevant to assure a safe and appropriate therapeutic administration of this drug.The effects of TAM on a variety of biological membranes have been reported to be a consequence of its biophysical and biochemical interactions with biomembranes (Custódio et al, 1993 that are related with its strong partition within the lipid bilayer (Custódio et al, 1991). Such effects include the stimulation of ATP hydrolysis and the decrease in the energetic efficiency of the Ca 2ϩ pump of sarcoplasmic reticulum , modifications in the morphology and structure of the breast tumor cell membranes, potentially responsible for its estrogenindependent antiproliferative activity (Sica et al, 1984), hemolytic effects (Cruz Silva et al, 2000), and mitochondrial swelling (Custódio et al, 1998).…”

mentioning

confidence: 99%

“…The effects of TAM on a variety of biological membranes have been reported to be a consequence of its biophysical and biochemical interactions with biomembranes (Custódio et al, 1993 that are related with its strong partition within the lipid bilayer (Custódio et al, 1991). Such effects include the stimulation of ATP hydrolysis and the decrease in the energetic efficiency of the Ca 2ϩ pump of sarcoplasmic reticulum , modifications in the morphology and structure of the breast tumor cell membranes, potentially responsible for its estrogenindependent antiproliferative activity (Sica et al, 1984), hemolytic effects (Cruz Silva et al, 2000), and mitochondrial swelling (Custódio et al, 1998).…”

mentioning

confidence: 99%

See 4 more Smart Citations

Mechanisms of the Deleterious Effects of Tamoxifen on Mitochondrial Respiration Rate and Phosphorylation Efficiency

Cardoso

Custódio

Almeida

et al. 2001

Toxicology and Applied Pharmacology

Self Cite

View full text Add to dashboard Cite

Tamoxifen (TAM), the widely prescribed drug in the prevention and therapy of breast cancer, is a well-known modulator of estrogen receptor (ER) that also inhibits the proliferation of different cell types that lack the ER. However, the ER-independent action mechanisms of TAM and its side effects have not been yet clarified. Mitochondria are essential in supporting the energy-dependent regulation of cell functions. Changes in mitochondria result in bioenergetic deficits leading to the loss of vital functions to cell survival. Therefore, this study describes the effects of TAM on mitochondrial bioenergetics, contributing to a better understanding of the biochemical mechanisms underlying the multiple antiproliferative and toxic effects of this drug. TAM at concentrations above 20 nmol/mg protein, preincubated with isolated rat liver mitochondria at 25°C for 3 min, significantly depresses, in a dose-dependent manner, the phosphorylation efficiency of mitochondria as inferred from the decrease in the respiratory control and ADP/O ratios, the perturbations in mitochondrial transmembrane potential (⌬⌿), the fluctuations associated with mitochondrial energization, and the phosphorylative cycle induced by ADP. Furthermore, TAM at up to 40 nmol/mg protein stimulates the rate of state 4 respiration and at higher concentrations it strongly inhibits state 3 and uncouples the mitochondrial respiration. The stimulation of state 4 respiration parallels the decrease of ⌬⌿ as a consequence of proton permeability. The TAM-stimulatory action of ATPase is also observed in intact mitochondria, suggesting that TAM promotes extensive permeability to protons due to destructive effects in the structural integrity of the mitochondrial inner membrane. These multiple effects of TAM on mitochondrial bioenergetic functions, causing changes in the respiration, phosphorylation efficiency, and membrane structure, may explain the cell death induced by this drug in different cell types, its anticancer activity in ER-negative cells, and its side effects. © 2001 Academic Press Key Words: tamoxifen; anticancer drug; mitochondria; respiration rate; mitochondrial transmembrane potential; mitochondrial proton leak; membrane disruption.Tamoxifen (TAM) is the most used nonsteroidal antiestrogen drug for chemotherapy and chemoprevention of breast cancer (Neven and Vernaeve, 2000;Radmacher and Simon, 2000). The antiproliferative effects of TAM in estrogen-dependent breast cancer cells are mediated by high-affinity binding to the estrogen receptor (ER) (Coezy et al., 1982). However, TAM inhibits also the growth of ER-negative breast cancer cells and other cell types that lack ER (Couldwell et al., 1993;Croxtall et al., 1994;Charlier et al., 1995). Actually, TAM has been reported to have several physiological effects that are ER independent, including sensitization of resistant tumor cells to many chemotherapeutic agents (Altan et al., 1999) and several pleiotropic effects both in vivo and in vitro and references therein). Moreover, it has been reported that...

show abstract

Section: Methodsmentioning

confidence: 99%

Section: Fig 5 Effects Of Tam (-) Andmentioning

confidence: 99%

mentioning

confidence: 95%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 3 more Smart Citations

Mechanisms of the Deleterious Effects of Tamoxifen on Mitochondrial Respiration Rate and Phosphorylation Efficiency

Cardoso

Custódio

Almeida

et al. 2001

Toxicology and Applied Pharmacology

Self Cite

View full text Add to dashboard Cite

show abstract

Confocal Raman microscopy for simultaneous monitoring of partitioning and disordering of tricyclic antidepressants in phospholipid vesicle membranes

Fox

Harris

2009

J Raman Spectroscopy

View full text Add to dashboard Cite

Characterization of drug-membrane interactions is important in order to understand the mechanisms of action of drugs and to design more effective drugs and delivery vehicles. Raman spectra provide compositional and conformational information of drugs and lipid membranes, respectively, allowing membrane disordering effects and drug partitioning to be assessed. Traditional Raman spectroscopy and other widely used bioanalytical techniques such as differential scanning calorimetry (DSC) and nuclear magnetic resonance (NMR) typically require high sample concentrations. Here, we describe how temperature-controlled, optical-trapping confocal Raman microscopy facilitates the analysis of drug-membrane interactions using micromolar concentrations of drug, while avoiding drug depletion from solution by working at even lower lipid concentrations. The potential for confocal Raman microscopy as an effective bioanalytical tool is illustrated using tricyclic antidepressants (TCAs), which are cationic amphiphilic molecules that bind to phospholipid membranes and influence lipid phase transitions. The interaction of these drugs with vesicle membranes of differing head-group charge is investigated while varying the ring and side-chain structure of the drug. Changes in membrane structure are observed in Raman bands that report intra-and intermolecular order versus temperature. The partitioning of drugs into the membrane can also be determined from the Raman scattering intensities. These results demonstrate the usefulness of confocal Raman microscopy for the analysis of drug-membrane systems at biologically relevant drug concentrations. Effective tools for monitoring drug-membrane interactions are crucial for rational design of new drugs.

show abstract

Novel Functional Hyperbranched Polyether Polyols as Prospective Drug Delivery Systems

Tziveleka

Kontoyianni

Sideratou

et al. 2006

Macromolecular Bioscience

View full text Add to dashboard Cite

Multifunctional hyperbranched polyether polyols bearing protective poly(ethylene glycol) (PEG) chains with or without the folate targeting ligand at their end have been prepared. Solubilization in these polymers of a fluorescent probe, pyrene, and an anticancer drug, tamoxifen, was physicochemically investigated. It was found that PEG chains attached at the surface of these hyperbranched polymers, in addition to their well-established protective role, enhance the encapsulation efficiency of the polymers. The release of pyrene and tamoxifen observed upon addition of sodium chloride is, in most of the cases, significant only at concentrations exceeding the physiological extracellular concentration. Thus, a significant amount of the probe or drug remains solubilized inside the carriers, which is an encouraging result if the polymers are to be used for drug delivery.

show abstract

A reliable and rapid procedure to estimate drug partitioning in biomembranes

Cited by 66 publications

References 24 publications

Mechanisms of the Deleterious Effects of Tamoxifen on Mitochondrial Respiration Rate and Phosphorylation Efficiency

Mechanisms of the Deleterious Effects of Tamoxifen on Mitochondrial Respiration Rate and Phosphorylation Efficiency

Confocal Raman microscopy for simultaneous monitoring of partitioning and disordering of tricyclic antidepressants in phospholipid vesicle membranes

Novel Functional Hyperbranched Polyether Polyols as Prospective Drug Delivery Systems

Contact Info

Product

Resources

About