Cellular Membranes and Lipid-Binding Domains as Attractive Targets for Drug Development

Sudhahar, Christopher G.; Haney, Rachel M.; Xue, Yi; Stahelin, Robert V.

doi:10.2174/138945008785132420

Cited by 33 publications

(31 citation statements)

References 96 publications

(131 reference statements)

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“…Membrane fluidity is a physicochemical feature of cell membranes that plays an important role in modulating RBC functions such as permeability, transport of ions or oxygen, membrane-associated enzyme activities and osmotic fragility (Derby and Gleeson 2007;Shinitzky 1984;Sudhahar et al 2008). Thus, maintaining adequate erythrocyte membrane fluidity levels is essential for optimal cell physiology.…”

Section: Discussionmentioning

confidence: 99%

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Erythrocyte membrane fluidity and indices of plasmatic oxidative damage after acute physical exercise in humans

et al. 2010

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Optimal levels of membrane fluidity are essential for numerous cell functions including cell growth, solute transport and signal transduction. Since exercise enhances free radical production, our aim was to evaluate in healthy male subjects the effects of an acute bout of maximal and submaximal exercise on the erythrocyte membrane fluidity and its possible relation to the oxidative damage overproduction due to exercise. Subjects (n = 34) performed three cycloergometric tests: a continuous progressive exercise, a strenuous exercise until exhaustion and an acute bout of exercise at an intensity corresponding to 70% of maximal work capacity for 30 min. Venous blood samples were collected before and immediately after these exercises. Erythrocyte membrane fluidity was assessed by fluorescence spectroscopy. Plasma malondialdehyde (MDA) and 4-hydroxyalkenals (4-HDA) concentrations and carbonyl content of plasmatic proteins were used as an index of lipid and protein oxidation, respectively. Exercise produced a dramatic drop in the erythrocyte membrane fluidity as compared to resting time, but this was not accompanied by significant changes in the plasmatic MDA and 4-HDA concentrations. The highest erythrocyte membrane rigidity was detected immediately after strenuous exercise until exhaustion was performed. Protein carbonyl levels were higher after exhaustive exercises than at rest. Continuous progressive and strenuous exercises until exhaustion, but not submaximal workload, resulted in a significant enhanced accumulation of carbonylated proteins in the plasma. These findings are consistent with the idea that exercise exaggerates oxidative damage, which may contribute, at least partially, to explain the rigidity in the membrane of the erythrocytes due to acute exercise.

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Section: Discussionmentioning

confidence: 99%

“…Numerous processes in or among cells, including signal transduction, solute transport and cell-cell interaction, are membrane mediated (Derby and Gleeson 2007;Sudhahar et al 2008). Cell membranes are complex bilayer structures compiled of a variety of lipids and proteins.…”

Section: Introductionmentioning

confidence: 99%

Erythrocyte membrane fluidity and indices of plasmatic oxidative damage after acute physical exercise in humans

et al. 2010

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“…The nature of bilayer lipid membranes (biomembranes) are infrequently mentioned in papers dealing with ion channels, even though biomembranes harbor receptors, ion channels (membrane proteins), lipid domains, lipid signals, and scaffolding complexes, which function to maintain cellular growth, metabolism, and homeostasis (Sudhahar et al 2008). In biomembranes, proteins recognize ester groups and headgroups such as choline, ethanolamine, and serine of the phospholipids and the hydroxyl and amide functions of the sphingomyelins.…”

Section: Biomembranes and Ion Channelsmentioning

confidence: 99%

Parameters for Pyrethroid Insecticide QSAR and PBPK/PD Models for Human Risk Assessment

Knaak

Dary²,

Zhang

et al. 2012

Reviews of Environmental Contamination and Toxicology

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In this review we have examined the status of parameters required by pyrethroid QSAR-PBPK/PD models for assessing health risks. In lieu of the chemical,biological, biochemical, and toxicological information developed on the pyrethroids since 1968, the finding of suitable parameters for QSAR and PBPK/PD model development was a monumental task. The most useful information obtained came from rat toxicokinetic studies (i.e., absorption, distribution, and excretion), metabolism studies with 14C-cyclopropane- and alcohol-labeled pyrethroids, the use of known chiral isomers in the metabolism studies and their relation to commercial products. In this review we identify the individual chiralisomers that have been used in published studies and the chiral HPLC columns available for separating them. Chiral HPLC columns are necessary for isomer identification and for developing kinetic values (Vm,, and Kin) for pyrethroid hydroxylation. Early investigators synthesized analytical standards for key pyrethroid metabolites, and these were used to confirm the identity of urinary etabolites, by using TLC. These analytical standards no longer exist, and muste resynthesized if further studies on the kinetics of the metabolism of pyrethroids are to be undertaken.In an attempt to circumvent the availability of analytical standards, several CYP450 studies were carried out using the substrate depletion method. This approach does not provide information on the products formed downstream, and may be of limited use in developing human environmental exposure PBPK/PD models that require extensive urinary metabolite data. Hydrolytic standards (i.e., alcohols and acids) were available to investigators who studied the carboxylesterase-catalyzed hydrolysis of several pyrethroid insecticides. The data generated in these studies are suitable for use in developing human exposure PBPK/PD models.Tissue:blood partition coefficients were developed for the parent pyrethroids and their metabolites, by using a published mechanistic model introduced by Poulin and Thiele (2002a; b) and log DpH 7.4 values. The estimated coefficients, especially those of adipose tissue, were too high and had to be corrected by using a procedure in which the proportion of parent or metabolite residues that are unbound to plasma albumin is considered, as described in the GastroPlus model (Simulations Plus, Inc.,Lancaster, CA). The literature suggested that Km values be adjusted by multiplying Km by the substrate (decimal amount) that is unbound to microsomal or CYPprotein. Mirfazaelian et al. (2006) used flow- and diffusion-limited compartments in their deltamethrin model. The addition of permeability areas (PA) having diffusion limits, such as the fat and slowly perfused compartments, enabled the investigators to bring model predictions in line with in vivo data.There appears to be large differences in the manner and rate of absorption of the pyrethroids from the gastrointestinal tract, implying that GI advanced compartmental transit models (ACAT) need to be included in PBPK mo...

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“…Moreover, abnormalities in lipid metabolism attributed to genetic changes among other causes are often associated with diseases such as cancer (1). Thus, there is a need to understand molecular events occurring within and on membranes as a means of grasping disease etiology and identifying viable targets for drug development (2). The lipid bilayer has a highly polarized structure that consists of a central hydrocarbon core and 2 flanking interfacial regions that are highly dynamic and may contain .1,000 different lipids (3).…”

Section: : S299-s304mentioning

confidence: 99%

Lipid binding domains: more than simple lipid effectors

Stahelin

2009

Journal of Lipid Research

123

105

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The spatial and temporal regulation of lipid molecules in cell membranes is a hallmark of cellular signaling and membrane trafficking events. Lipid-mediated targeting provides for strict control and versatility, because cell membranes harbor a large number of lipid molecules with variation in head group and acyl chain structures. Signaling and trafficking proteins contain a large number of modular domains that exhibit specific lipid binding properties and play a critical role in their localization and function. Nearly 20 years of research including structural, computational, biochemical and biophysical studies have demonstrated how these lipid-binding domains recognize their target lipid and achieve subcellular localization. The integration of this individual lipid-binding domain data in the context of the fulllength proteins, macromolecular signaling complexes, and the lipidome is only beginning to be unraveled and represents a target of therapeutic development. This review brings together recent findings and classical concepts to concisely summarize the lipid-binding domain field while illustrating where the field is headed and how the gaps may be filled in with new technologies.-Stahelin, R. V. Lipid binding domains: more than simple lipid effectors. J. Lipid Res. 2009. 50: S299-S304.

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Cellular Membranes and Lipid-Binding Domains as Attractive Targets for Drug Development

Cited by 33 publications

References 96 publications

Erythrocyte membrane fluidity and indices of plasmatic oxidative damage after acute physical exercise in humans

Erythrocyte membrane fluidity and indices of plasmatic oxidative damage after acute physical exercise in humans

Parameters for Pyrethroid Insecticide QSAR and PBPK/PD Models for Human Risk Assessment

Lipid binding domains: more than simple lipid effectors

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