Do low molecular weight antioxidants contribute to the Protection against oxidative damage? The interrelation between oxidative stress and low molecular weight antioxidants based on data from the MARK-AGE study.

A redox steady state is important in maintaining vital cellular functions and is therefore homeostatically controlled by a number of antioxidative agents, the most important of which are enzymes. Oxidative Stress (OS) is associated with (or/and caused by) excessive production of damaging reactive oxygen and/or nitrogen species (ROS, RNS), which play a role in many pathologies. Because OS is a risk factor for many diseases, much effort (and money) is devoted to early diagnosis and treatment of OS. The desired benefit of the "identify (OS) and treat (by low molecular weight antioxidants, LMWA)" approach is to enable selective treatment of patients under OS. The present work aims at gaining understanding of the benefit of the antioxidants based on interrelationship between the concentration of different OS biomarkers and LMWA. Both the concentrations of a variety of biomarkers and of LMWA were previously determined and some analyses have been published by the MARK-AGE team. For the sake of simplicity, we assume that the concentration of an OS biomarker is a linear function of the concentration of a LMWA (if the association is due to causal relationship). A negative slope of this dependence (and sign of the correlation coefficient) can be intuitively expected for an antioxidant, a positive slope indicates that the LMWA is pro-oxidative, whereas extrapolation of the OS biomarker to [LMWA] = 0 is an approximation of the concentration of the OS biomarker in the absence of the LMWA. Using this strategy, we studied the effects of 12 LMWA (including tocopherols, carotenoids and ascorbic acid) on the OS status, as observed with 8 biomarkers of oxidative damage (including malondialdehyde, protein carbonyls, 3-nitrotyrosine). The results of this communication show that in a cross-sectional study the LMWA contribute little to the redox state and that different "antioxidants" are very different, so that single LMWA treatment of OS is not scientifically justified assuming our simple model. In view of the difficulty of quantitating the OS and the very different effects of various LMWA, the use of the "identify and treat" approach is questionable.

Detergent solubilization of lipid bilayers: a balance of driving forces.

Although detergents are routine tools in biomembrane research, their use remains empirical. We propose that solubilization is the result of a balance between two parameters: (i) the energy associated with bending of phospholipid monolayers into a curved micellar surface, and (ii) the energy associated with filling the void in the center of the resultant mixed micelle. In this review, we show that reliable data on the phase boundaries, and their dependence on various conditions, are consistent with this hypothesis, even if the data might have been interpreted differently. Although most of the experimental data discussed here were obtained with the non-ionic detergent Triton X-100, the conclusions should be applicable to a wide variety of detergents.

Oxidative stress, the term and the concept.

The 30th birthday of a central concept in biomedicine, such as oxidative stress (OS) is a good time for re-evaluation of its contribution to science and particularly to the field of redox biology. In his recent communication, Sies described the history of the concept as well as the benefits and pitfalls of the term OS. In this mini-review, we discuss the problems associated with the still common perception of "bad OS, good antioxidants". Specifically, the term OS is an intuitively understood term originally used to describe an imbalance between pro-oxidative factors and anti-oxidative factors. It has no units, its level is dependent on the way it is measured and there is no correlation between various criteria of OS, which indicates that there are sub-classes (types) of OS (other than the classifications presented by Sies). In spite of these limitations, it is commonly regarded a measure of a person's probability to suffer from oxidative damages and is being held responsible for many diseases and antioxidants are predicted to be good to us. In fact, a "Basal OS" is vital and antioxidants may interfere with the mechanisms responsible for maintaining the oxidative status. We also discuss the linkage of OS to the outcome of antioxidant supplementation and comment on the importance of kinetic studies in evaluation of OS and on the ranking of antioxidants.

The mechanism of detergent solubilization of lipid bilayers.

Multiple data are available on the self-assembly of mixtures of bilayer-forming amphiphiles, particularly phospholipids and micelle-forming amphiphiles, commonly denoted detergents. The structure of such mixed assemblies has been thoroughly investigated, described in phase diagrams, and theoretically rationalized in terms of the balance between the large spontaneous curvature of the curvophilic detergent and the curvophobic phospholipids. In this critical review, we discuss the mechanism of this process and try to explain the actual mechanism involved in solubilization. Interestingly, membrane solubilization by some detergents is relatively slow and the common attribute of these detergents is that their trans-bilayer movement, commonly denoted flip-flop, is very slow. Only detergents that can flip into the inner monolayer cause relatively rapid solubilization of detergent-saturated bilayers. This occurs via the following sequence of events: 1), relatively rapid penetration of detergent monomers into the outer monolayer; 2), trans-membrane equilibration of detergent monomers between the two monolayers; 3), saturation of the bilayer by detergents and consequent permeabilization of the membrane; and 4), transition of the whole bilayer to thread-like mixed micelles. When the detergent cannot flip to the inner monolayer, the outer monolayer becomes unstable due to mass imbalance between the monolayers and inclusion of the curvophilic detergent molecules in a flat surface. Consequently, the outer monolayer forms mixed micellar structures within the outer monolayer. Shedding of these micelles into the aqueous solution results in partial solubilization. The consequent leakage of detergent into the liposome results in trans-membrane equilibration of detergent and subsequent micellization through the rapid bilayer-saturation mechanism.

Oxidative Stress Is a Concept, Not an Indication for Selective Antioxidant Treatment.

The steady-state redox status is physiologically important and therefore homeostatically maintained. Changes in the status result in signaling (eustress) or oxidative damage (distress). Oxidative stress (OS) is a hard-to-quantitate term that can be estimated only based on different biomarkers. Clinical application of OS, particularly for selective antioxidant treatment of people under oxidative stress, requires quantitative evaluation and is limited by the lack of universal biomarkers to describe it. Furthermore, different antioxidants have different effects on the redox state. Hence, as long as we do not have the possibility to determine and quantify OS, therapeutic interventions by the "identify-and-treat" approach cannot be assessed and are, therefore, not likely to be the basis for selective preventive measures against oxidative damage.

[Who is likely to gain from high dose supplementation of vitamin E?].

Given the assumption that oxidative stress plays a pivotal role in atherogenesis, it could have been predicted that antioxidants will slow or even stop the development of atherotic plaques. The results of the latter prediction were disappointing. Moreover, previous meta-analyses concluded that indiscriminate supplementation of vitamin E at high dose (400 IU or more) results in increased mortality, both cardiovascular and all-cause. This conclusion raised serious criticisms, particularly on the choice of studies for meta-analyses, the end point (mortaLity) and the heterogeneity of the clinicaL studies with respect to both the population and the treatment. In Dr. Dotan's PhD thesis, conducted under my supervision, with the assistance of Drs. Leshno and Pinchuk, we analysed the results of the major cLinicaL studies within a Markov model. Using this approach enabled us to adjust the data for heterogeneities and assess the sensitivity of the outcome to the different affectors. The adjusted data were then used to assess the risk of transitions between predefined health state (healthy, dead or CVD patients, following a cardiac event). We also used a different 'end point', that is the quantity-adjusted life years (QALY), which reflects both morbidity and mortality. The major result of this study is that indiscriminate high dose supplementation of vitamin E is associated with an average loss of about 0.3 QALY. Yet, we think that some specific groups (presumably those that suffer from high oxidative stress) may gain from vitamin E supplementation. The existing data is insufficient to predict who is likely to benefit from vitamin E treatment. Until such data becomes available, we cannot recommend high dose vitamin E supplementation.

Decision analysis supports the paradigm that indiscriminate supplementation of vitamin E does more harm than good.

OBJECTIVE: For many years, the prevailing concept was that LDL oxidation plays a central role in atherogenesis. As a consequence, supplementation of antioxidants, particularly vitamin E, became very popular. Unfortunately, however, the major randomized clinical trials have yielded disappointing results on the effects of vitamin E on both mortality and morbidity. Moreover, recent meta-analyses have concluded that vitamin E supplementation increases mortality. This conclusion has raised much criticism, most of it relating to three issues: (1) the choice of clinical trials to be included in the meta-analyses; (2) the end point of these meta-analyses (only mortality); and (3) the heterogeneity of the analyzed clinical trials with respect to both population and treatment. Our goal was to bring this controversy to an end by using a Markov-model approach, which is free of most of the limitations involved in using meta-analyses. METHODS AND RESULTS: We used a Markov model to compare the vitamin E supplemented virtual cohorts with nonsupplemented cohorts derived from published randomized clinical trials that were included in at least one of the major meta-analyses. The difference between the virtual supplemented and nonsupplemented cohorts is given in terms of a composite end point denoted quality-adjusted life year (QALY). The vitamin E supplemented virtual cohort had 0.30 QALY (95%CI 0.21 to 0.39) less than the nontreated virtual cohort. CONCLUSIONS: Our study demonstrates that in terms of QALY, indiscriminate supplementation of high doses of vitamin E is not beneficial in preventing CVD. Selective supplementation of vitamin E to individuals under oxidative stress requires further investigation.

[Medical training in Israel--can we realize the comments of Pazi's Committee and at what cost?].

In spite of the growth of Israel's population, the number of graduates from the four Israeli Schools of Medicine has changed very little in the last 30 years. Nevertheless, the annual number of new practitioners grew from about 300 to 900, due to Israeli graduates of European Schools and the large number of physicians among the new immigrants from the former USSR states in the early nineties. A committee, nominated by the National Board of Higher Education (MALAG), headed by the late Prof. Pazi, concluded that under steady state conditions we must train 800 medical students per year. MALAG adopted this recommendation. As a first step, MALAG approved two new programs: a special program for Academic Reserve candidates (Atudaim) and a new (5th) medical school in the Galilee. These two new programs, together with the new 4-year MD program in Tel Aviv, will add about 200 graduates to the list of medical students. Yet, the question of whether we can realize the recommendation of Pazi's Committee (to train 800 MDs annually) and at what cost, remains open. This preliminary review is devoted to the relevant factors that must be considered before the latter questions can be answered. First, we note that the limiting factor of the number of medical students is the ratio between the number of teaching departments in each of the medical disciplines and the number of weeks of Clerkships required in the given disciplines. Our main conclusion is that realization of the recommendation of Pazi's committee requires an increase in the number of teaching departments, preferably by upgrading the academic level of those departments that do not teach students, and increasing the teaching load of other departments. We may also have to reduce the number of weeks of 'bedside teaching' but should beware of reducing it to a minimum lower than about 70 weeks, as in North America. Regardless of the need to train more physicians, we must increase teaching in the community. Only a combination of all these measures will reduce our dependence on the education of Israeli physicians abroad.

Detergent-resistant membranes should not be identified with membrane rafts.

Three originally distinct concepts - lipid rafts, detergent-resistant membranes (DRMs) and liquid-ordered (lo) lipid phases - are often confused in current literature; many researchers have assumed that all three names refer to the same chemico-biological entity. In fact, theoretical and experimental findings provide strong evidence against identifying DRMs with rafts and lo domains. Because much of what we think we know about lipid rafts is based on their unjustified identification as DRMs, functional domains in biological membranes might differ markedly from the generally accepted picture.

Polyphenol-induced dissociation of various amyloid fibrils results in a methionine-independent formation of ROS.

Fibrillization of amyloid polypeptides is accompanied by formation of reactive oxygen species (ROS), which, in turn, is assumed to further promote amyloid-related pathologies. Different polyphenols, all of which are established antioxidants, cause dissociation of amyloid fibrils. This study addresses the latter, poorly understood process. Specifically, we have investigated the dissociation of Abeta(42) fibrils by six different polyphenols, using electron microscopy and spectrofluorometric analysis. Simultanously, we have monitored the production of ROS using electron spin resonance (ESR) and the commercially available peroxide assay kit. Using the same methods we found that curcumin, one of the most potent destabilizing agents of Abeta(42), induced dissociation of fibrils of other amyloid polypeptides [Abeta(40), Abeta(42)Nle35, islet amyloid polypeptide and a fragment of alpha-synuclein]. When the solution contained traces of transition metal, all the dissociation reactions were accompanied by ROS formation, independent of the presence of a methionine residue. Kinetic studies show that the formation of ROS lags behind dissociation, indicating that if casual relationship exists between these two processes, then ROS formation may be considered a consequence and not a cause of dissociation. These findings open new avenues in amyloid research that will be required to gain further understanding of our results and of their implications.

Gender- and age-dependencies of oxidative stress, as detected based on the steady state concentrations of different biomarkers in the MARK-AGE study.

Recently, Weber et al. published a thorough investigation of the age-dependency of oxidative stress (OS) determined by the steady state concentrations of different compounds - oxidation products and antioxidants - that are in common use as biomarkers of OS in 2207 healthy individuals of the cross-sectional MARK-AGE Project. The correlations among biomarkers were significant but weak. These findings may indicate different manifestations of OS and must further be evaluated. Here, we report a refined analysis of OS based on the above-mentioned original data. We show that malondialdehyde (MDA) appears to be sensitive to both gender and age. It is significantly lower and shows a greater age-dependence in women than in men. The age-dependency of MDA in women arises in a stepwise fashion. The age-dependent slope of the steady state concentration is maximal at the age between 50 and 55 years, indicating that it may be attributed to the change of metabolism in the post-menopause. Interestingly, total glutathione (GSH) decreased with age simultaneously with the increase in MDA. Different biomarkers yield different gender- and age-dependencies. Unlike the concentration of MDA, the concentrations of the other two oxidation products, i.e. protein carbonyls and 3-nitrotyrosine were similar in men and women and appeared to be independent of age in the healthy study population. The analyzed antioxidants exhibited different gender- and age-dependencies. In conclusion, it appears that all the biomarkers assessed here reflect different types of OS and that MDA and GSH reflect the same type of OS.

MOR: a simulation-based assessment centre for evaluating the personal and interpersonal qualities of medical school candidates.

CONTEXT: Medical school admissions traditionally rely heavily on cognitive variables, with non-cognitive measures assessed through interviews only. In recognition of the unsatisfactory reliability and validity of traditional interviews, medical schools are increasingly exploring alternative approaches that can provide improved measures of candidates' personal and interpersonal qualities. METHODS: An innovative assessment centre (MOR [Hebrew acronym for 'selection for medicine']) was designed to measure candidates' personal and interpersonal attributes. Three assessment tools were developed: behavioural stations, including encounters with simulated patients and group tasks; an autobiographical questionnaire, and a judgement and decision-making questionnaire. Candidates were evaluated by trained raters on four qualities: interpersonal communication; ability to handle stress; initiative and responsibility, and self-awareness. RESULTS: In the years 2004-05, the 588 medical school candidates with the highest cognitive scores were tested; this resulted in a change of approximately 20% in the cohort of accepted students compared with previous admission criteria. Internal consistency ranged from 0.80 to 0.88; inter-rater reliability ranged from 0.62 to 0.77 for the behavioural stations and from 0.72 to 0.95 for the questionnaires; test-retest score correlation was 0.7. The correlation between candidates' MOR scores and cognitive scores approached zero, reflecting the value of MOR in the screening process. Feedback from participants indicated that MOR was perceived as fair and appropriate for medical school screening. DISCUSSION: MOR is a reliable tool for measuring non-cognitive attributes in medical school candidates. It has high content and face validity. Furthermore, its implementation conveys the importance of maintaining humanist characteristics in the medical profession to students and faculty staff.

Oxidative stress, as assayed by a single test, cannot be used as a diagnostic tool.

The commonly used term "oxidative stress" (OS) is intuitively defined as an excess of pro-oxidative compounds, over antioxidants. The redox status is homeostatically controlled because on one hand, pro-oxidants are essential for normal body function, whereas, on the other hand, pro-oxidants (and OS) are associated with many diseases due to the risk of oxidative damage. One reason "to monitor the OS" is to identify people under OS and treat people under high OS by antioxidants, because it is believed that people under OS benefit from antioxidant supplementation more than others. This approach led to the production of many assay kits, based on the concentrations of different biomarkers in body fluids. Unfortunately, this expensive approach (evaluated at about a half a billion dollars per year) yields very limited results because: (i) the effect of antioxidants on the OS is not that simple and (ii) OS cannot be quantitated in terms of a universal criterion and the method-dependent OS yields different groups of people under OS. This conclusion gains strong support from analysis of the results of a previous study of the OS in more than 2000 participants, using many OS assays. The small overlapping between the "people under OS" as assayed by different biomarkers clearly shows that OS cannot be used as a diagnostic tool. © 2018 BioFactors, 44(3):222-223, 2018.

The molecular mechanisms of the anti-amyloid effects of phenols.

Previous investigations demonstrated that various aromatic compounds, many of which are known antioxidants, inhibit amyloid fibril formation. Yet, the mechanism of action of these compounds is not fully understood and contribution of their antioxidative potency has not been addressed. In recent publications, Ono et al. (2003, 2004) studied the anti-amyloid effects of 11 phenols on each of three consecutive processes: (1) seeding (formation) of nascent fibrils, (2) elongation (extension) of the fibrils, and (3) depolymerization (destabilization) of the formed assemblies. The aim of the present study was to evaluate the molecular mechanisms that mediate the effects of the studied inhibitors on each of these processes. Hierarchical clustering analyses indicated that the studied inhibitors can be categorized into three groups: 'slightly active' inhibitors, 'highly active' inhibitors and 'selective inhibitors' that differ markedly in their effects on these three stages. Analyses of the correlations between the effects of the studied compounds on the various stages of amyloid fibril formation, and their known physicochemical properties provided novel insights on the specific role of hydrophobic and aromatic interactions as well as the antioxidative potency on the process of amyloid fibril formation and dissociation. Specifically, the hydrophobic and/or aromatic character of the compounds makes the major contribution to the anti-formation and anti-extension effects, whereas the antioxidative potency relates mostly to the promotion of destabilization.

Serum lipid oxidizibility in term premature rupture of the membranes.

OBJECTIVE: In our previous studies we have shown that the process of term labor is associated with oxidative stress, as indicated by increased susceptibility of maternal serum lipids to copper induced peroxidation. In order to continue evaluating the role of oxidative stress in the labor process, we next tested whether term premature rupture of the membranes (PROM) is also associated with increased susceptibility of maternal serum lipids to copper induced peroxidation. DESIGN: A controlled prospective study. SETTING: Tertiary care centre. POPULATION: 31 healthy women with term PROM and 19 healthy pregnant women with intact membranes. The women were matched for maternal and gestational age. METHODS: Venous blood was drawn from the women (up to 6h after rupture of the membranes and prior to labor in the PROM group), and the kinetics of copper-induced oxidation of serum lipids ex vivo were monitored spectroscopically at 37 degrees C by continuous recording of absorbance at 245 nm. RESULTS: The lag phase, reflecting resistance of serum lipids to oxidation, was similar in the PROM group when compared to the control group (43.7+/-3.2 versus 41.9+/-1.6 min, P=0.61). However, the maximal rate of oxidation (V(max)) and the maximal accumulation of absorbing products (OD(max)) were shorter in the PROM group when compared to the control group (5.14+/-0.26 versus 6.29+/-0.4010(-3) OD(245) nm/min, P=0.016; 0.61+/-0.03 versus 0.71+/-0.04 OD(245) nm, P=0.07). CONCLUSION: As opposed to term labor, term PROM is not associated with increased maternal systemic oxidative stress when compared to normal pregnant women. The role for oxidative stress in preterm PROM warrants further studies.

Deuterium kinetic isotope effect (DKIE) in copper-induced LDL peroxidation: Interrelated effects of on inhibition and propagation.

LDL peroxidation plays a major role in many physiological and pathophysiological processes. The mechanisms of LDL peroxidation induced by transition metal ions have therefore been studied intensively. It has been proposed that the mechanism involves free radical production that occurs via decomposition of hydroperoxides. This, in turn, requires the cleavage of O-H bonds. Cleavage of O-D bond is slower and comparison of the kinetics in D2O to the kinetics in H2O is therefore a straightforward way to test this aspect of the alleged mechanism. The kinetics of peroxidation exhibit marked deuterium kinetic isotope effects at all the stages of oxidation under all the studied conditions. We found that the rate of propagation of copper-induced peroxidation is a monotonically decreasing function of D2O fraction in D2O/H2O mixtures. The only elementary reaction that involves "exchangeable" hydrogen at this stage is copper-induced decomposition of conjugated hydroperoxides. Therefore, we conclude that the latter step is rate-limiting reaction including cleavage of oxygen-hydrogen bond of hydroperoxide. The lag preceding rapid peroxidation exhibits a biphasic dependence on the fraction of D2O. This may be understood on the basis of the effect of substituting hydrogen atoms by deuterium. Specifically, such substitution is expected to decrease both the rate of initiation of peroxidation and the potency of the antioxidant. We interpret our results in terms of the effects of isotopic substitution on the rates of the reactions that involve the abstraction of "exchangeable" hydrogen atoms of OH groups in tocopherol and hydroperoxides.

Celecoxib and curcumin synergistically inhibit the growth of colorectal cancer cells.

PURPOSE: Multiple studies have indicated that cyclooxygenase-2 (COX-2) inhibitors may prevent colon cancer, which is one of the leading causes of cancer death in the western world. Recent studies, however, showed that their long-term use may be limited due to cardiovascular toxicity. This study aims to investigate whether curcumin potentiates the growth inhibitory effect of celecoxib, a specific COX-2 inhibitor, in human colon cancer cells. EXPERIMENTAL DESIGN: HT-29 and IEC-18-K-ras (expressing high levels of COX-2), Caco-2 (expressing low level of COX-2), and SW-480 (no expression of COX-2) cell lines were exposed to different concentrations of celecoxib (0-50 micromol/L), curcumin (0-20 micromol/L), and their combination. COX-2 activity was assessed by measuring prostaglandin E(2) production by enzyme-linked immunoassay. COX-2 mRNA levels were assessed by reverse transcription-PCR. RESULTS: Exposure to curcumin (10-15 micromol/L) and physiologic doses of celecoxib (5 micromol/L) resulted in a synergistic inhibitory effect on cell growth. Growth inhibition was associated with inhibition of proliferation and induction of apoptosis. Curcumin augmented celecoxib inhibition of prostaglandin E(2) synthesis. The drugs synergistically down-regulated COX-2 mRNA expression. Western blot analysis showed that the level of COX-1 was not altered by treatment with celecoxib, curcumin, or their combination. CONCLUSIONS: Curcumin potentiates the growth inhibitory effect of celecoxib by shifting the dose-response curve to the left. The synergistic growth inhibitory effect was mediated through a mechanism that probably involves inhibition of the COX-2 pathway and may involve other non-COX-2 pathways. This synergistic effect is clinically important because it can be achieved in the serum of patients receiving standard anti-inflammatory or antineoplastic dosages of celecoxib.

The mechanism of action of antioxidants against lipoprotein peroxidation, evaluation based on kinetic experiments.

Peroxidation of blood lipoproteins is regarded as a key event in the development of atherosclerosis. Hence, attenuation of the oxidative modification of lipoproteins by natural and synthetic antioxidants in vivo is considered a possible way of prevention of cardiovascular disorders. The assessment of the susceptibility of lipoproteins to oxidation is commonly based on in vitro oxidation experiments. Monitoring of oxidation provides the kinetic profile characteristic for the given lipoprotein preparation. The kinetic profile of peroxidation is characterized by three major parameters: the lag preceding rapid oxidation, the maximal rate of oxidation (V(max)) and the maximal accumulation of oxidation products (OD(max)). Addition of antioxidants alters this pattern, affecting the kinetic parameters of oxidation. In particular, antioxidants may prolong the lag and/or decrease the V(max) and/or decrease the OD(max). Such specific variation of the set of kinetic parameters may provide important information on the mechanism of the inhibitory action of a given antioxidant (scavenging free radicals, metal-binding or other mechanisms). Numerous natural and synthetic compounds were reported to inhibit oxidation of lipoproteins. Based on the analysis of reported effects and theoretical considerations, we propose a simple protocol that relates the kinetic effects of a given antioxidant to the mechanism of its action.

The effect of compartmentalization on the kinetics of transition metal ions-induced lipoprotein peroxidation.

In a previous study, we proposed characterizing the typically observed kinetic profiles of transition metal ion-induced lipid peroxidation in terms of a limited number of characteristic time-points. These time-points can be derived from experimental time-dependencies and be presented in terms of rate constants and concentrations as calculated based on mechanistic considerations. The critical part of that analysis was that we had to assume that the experimental system behaves as if it is homogeneous, i.e., as if the reaction occurs in a solution. In spite of the uncertainties due to the latter assumption, we obtained a reasonable agreement between the experimental data and the theoretically predicted dependencies, which supports our theoretical treatment. Yet, several previous findings could not have been explained in terms of our ('quasi-homogeneous') model, indicating that the model is valid not under all conditions. One example is that under certain conditions, rapid peroxidation occurs prior to complete consumption of LDL-associated tocopherol. This can be attributed to compartmentalization of residual tocopherol, namely, after the onset of propagation, part of the LDL particles contain tocopherol, whereas in the other, tocopherol-depleted particles, the PUFA may undergo rapid LOOH-accelerated peroxidation only if they contain at least two hydroperoxides molecules per particle. In the present investigation, we show that the results of all our kinetic studies can be understood if we consider compartmentalization. Specifically, for any given composition of the particles (LDL and/or HDL), the kinetic results may be governed by the distribution and rate of exchange of antioxidants and hydroperoxides between particles. Our analysis is of special importance for systems containing more than one population of lipoprotein particles.