1,2-Naphthoquinone Stimulates Lipid Peroxidation and Cholesterol Domain Formation in Model Membranes

Jacob, Robert F.; Aleo, Michael D.; Self-Medlin, Yehudi; Doshna, Colleen M.; Mason, R. Preston

doi:10.1167/iovs.13-12793

Cited by 11 publications

(8 citation statements)

References 72 publications

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“…Second, existing methods, because of the presence of other domains in intact membranes, could not discriminated CBDs. Our measurements (Mainali et al, 2013b; Raguz et al, 2011a, b) and data from the literature (Jacob et al, 2013; Jacob and Mason, 2005; Jin et al, 2018; Litz et al, 2016) indicate that, in model membranes, when the Chol content is close to or exceeds the Chol solubility threshold in PL bilayers, CBDs are always present. Additionally, the formation of CBDs precedes the formation of Chol crystals (Mainali et al, 2013b).…”

Section: Discussionsupporting

confidence: 60%

Detection of cholesterol bilayer domains in intact biological membranes: Methodology development and its application to studies of eye lens fiber cell plasma membranes

Mainali

O’Brien

Subczynski

2019

Experimental Eye Research

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Four purported lipid domains are expected in plasma membranes of the eye lens fiber cells. Three of these domains, namely, bulk, boundary, and trapped lipids, have been detected. The cholesterol bilayer domain (CBD), which has been detected in lens lipid membranes prepared from the total lipids extracted from fiber cell plasma membranes, has not yet been detected in intact fiber cell plasma membranes. Here, a saturation-recovery electron paramagnetic resonance spin-labeling method has been developed that allows identification of CBDs in intact fiber cell plasma membranes of eye lenses. This method is based on saturation-recovery signal measurements of the cholesterol-analog spin label located in the lipid bilayer portion of intact fiber cell membranes as a function of the partial pressure of molecular oxygen with which the samples are equilibrated. The capabilities and limitations of this method are illustrated for intact cortical and nuclear fiber cell plasma membranes from porcine eye lenses where CBDs were detected in porcine nuclear intact membranes for which CBDs were also detected in lens lipid membranes. CBDs were not detected in porcine cortical intact and lens lipid membranes. CBDs were detected in intact membranes isolated from both cortical and nuclear fiber cells of lenses obtained from human donors. The cholesterol content in fiber cell membranes of these donors was always high enough to induce the formation of CBDs in cortical as well as nuclear lens lipid membranes. The results obtained for intact membranes, when combined with those obtained for lens lipid membranes, advance our understanding of the role of high cholesterol content and CBDs in lens biology, aging, and/or cataract formation.

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Section: Discussionsupporting

confidence: 60%

Detection of cholesterol bilayer domains in intact biological membranes: Methodology development and its application to studies of eye lens fiber cell plasma membranes

Mainali

O’Brien

Subczynski

2019

Experimental Eye Research

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“…To conclude, we reiterate that the proposed hypothesis has already been tested in its basic sense. The published experimental results show that (1) formation of CBDs in liposomal membranes precedes formation of Chol crystals (e.g., [17,18,20,30,31]), and (2) Chol crystals can be formed from membrane Chol (without the external addition of Chol) when the Chol solubility threshold in the membrane is decreased, for example, by lipid peroxidation [21][22][23]. Based on the saturation recovery EPR technique, we are planning to design an experimental procedure to quantitatively estimate the average amount of Chol in a CBD at the saturation threshold in bilayers made of polyunsaturated phospholipids (before peroxidation).…”

Section: Discussionmentioning

confidence: 99%

“…[37]. It has been also shown that phospholipid peroxidation decreases to a considerable extent the Chol concentrations at which formation of CBDs [21,22] and Chol crystals [31] are initiated. Peroxidation mainly involves the polyunsaturated chain and introduces a hydroperoxide group into the chain at a double-bond position.…”

Section: Chol and Phospholipid Oxidation As Factors Affecting Chol Samentioning

confidence: 97%

“…A further increase of Chol content above the Chol solubility threshold induces formation of Chol crystals [17][18][19][20]. The peroxidation of phospholipids in a membrane containing a large amount of Chol does not change the relative proportion of Chol and phospholipids; however, it lowers the amount of Chol needed for CBDs to start to form [21][22][23]. Thus, conditions driving the development of atherosclerosis (high-Chol level and oxidative stress) lead to the situation wherein a membrane oversaturated with Chol is no longer able to accommodate some or all of the CBDs, so the CBDs detach from the membrane and collapse (i.e., fall out of the membrane either inside or outside of the cell) in the form of Chol aggregates that can become crystal nuclei and, in time, convert into Chol monohydrate crystals.…”

Section: A New Hypothetical Pathway Leading To the Formation Of Cholementioning

confidence: 99%

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Hypothetical Pathway for Formation of Cholesterol Microcrystals Initiating the Atherosclerotic Process

Subczynski

Pasenkiewicz-Gierula

2020

Cell Biochem Biophys

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Major factors leading to the development of atherosclerosis are a high cholesterol (Chol) level in the blood and oxidative stress. Both promote the formation of Chol microcrystals in blood vessel walls. Deposition of Chol microcrystals in arterial intima causes inflammation, which initiates and accompanies the atherosclerotic process in all its phases. One of the possible sources of Chol in the blood vessel walls is oxidized low-density lipoproteins—this atherosclerotic plaque formation pathway has already been described in the literature. Here, we hypothesize that initiation of the atherosclerotic process may involve Chol domains in the plasma membranes of arterial cells. Increased Chol content and the presence of polyunsaturated phospholipids in these membranes together with oxidative stress (phospholipid peroxidation) may lead to the formation of pure Chol bilayer domains that, with further peroxidation and increased Chol content, may collapse in the form of Chol seed crystals. Independent of their origin, Chol microcrystals activate inflammasomes, thereby stimulate immune responses, and initiate inflammation that may lead to the development of atherosclerosis. This new, hypothetical pathway has not yet been investigated in depth; however, data from the literature and our own results support its feasibility.

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“…In our portfolio experience, CP‐03504992 and CP‐642,931, but not its pharmacological pair, CP‐470,711, promoted cholesterol domain formation in rat brain sphingomyelin membranes (data not shown), suggesting disruptions on proper cholesterol biosynthesis and cholesterol domain formation as important independent contributors to cataract formation, which is a known feature of cataractous lenses (Jacob et al, ). Other known cataractogens such as U18666A and 1,2‐naphthoquinone, the reactive metabolite of naphthalene, also promote cholesterol domain formation through oxidative stress (Cenedella, ; Cenedella et al, ; Jacob, Aleo, Self‐Medlin, Doshna, & Mason, ).…”

Section: Discussionmentioning

confidence: 99%

Lens cholesterol biosynthesis inhibition: A common mechanism of cataract formation in laboratory animals by pharmaceutical products

Aleo¹,

Doshna²,

Baltrukonis³

et al. 2019

J of Applied Toxicology

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CJ-12,918, a 5-lipoxygenase (5-LO) inhibitor, caused cataracts during a 1-month safety assessment studies in rats whereas the structurally similar ZD-2138 was without effect. For CJ-12,918 analogs, blocking different sites of metabolic liability reduced (CJ-13,454) and eliminated (CJ-13,610) cataract formation in both rats and dogs. Using this chemical series as a test set, models and mechanisms of toxicity were first explored by testing the utility of ex vivo rat lens explant cultures as a safety screen. This model overpredicted the cataractogenic potential of ZD-2138 due to appreciably high lens drug levels and was abandoned in favor of a mechanismbased screen. Perturbations in lens sterol content, from a decline in lathosterol content, preceded cataract formation suggesting CJ-12,918 inhibited lens cholesterol biosynthesis (LCB). A 2-day bioassay in rats using ex vivo LCB assessments showed that the level of LCB inhibition was correlated with incidence of cataract formation in animal studies by these 5-LO inhibitors. Thereafter, this 2-day bioassay was applied to other pharmaceutical programs (neuronal nitric oxide synthase, sorbitol dehydrogenase inhibitor, squalene synthetase inhibitor and stearoyl-CoA desaturase-1 inhibitors/D 4 antagonists) that demonstrated cataract formation in either rats or dogs. LCB inhibition >40% was associated with a high incidence of cataract formation in both rats and dogs that was species specific. Bioassay sensitivity/specificity were further explored with positive (RGH-6201/ciglitazone/U18666A) and negative (tamoxifen/naphthalene/galactose) mechanistic controls. This body of work over two decades shows that LCB inhibition was a common mechanism of cataract formation by pharmaceutical agents and defined a level of inhibition >40% that was typically associated with causing cataracts in safety assessment studies typically ≥1 month.

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1,2-Naphthoquinone Stimulates Lipid Peroxidation and Cholesterol Domain Formation in Model Membranes

Abstract: These data suggest a novel mechanism for naphthalene-induced cataract, facilitated by the direct effects of 1,2-NQ on lipid peroxidation and cholesterol domain formation.

Cited by 11 publications

References 72 publications

Detection of cholesterol bilayer domains in intact biological membranes: Methodology development and its application to studies of eye lens fiber cell plasma membranes

Detection of cholesterol bilayer domains in intact biological membranes: Methodology development and its application to studies of eye lens fiber cell plasma membranes

Hypothetical Pathway for Formation of Cholesterol Microcrystals Initiating the Atherosclerotic Process

Lens cholesterol biosynthesis inhibition: A common mechanism of cataract formation in laboratory animals by pharmaceutical products

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