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PubMed1980

The embryotoxicity of the cyclophosphamide metabolite acrolein in rabbits, tested in vivo by i.v. injection and by the yolk-sac method.

On the 9th day of gestation the embryotoxic effects of acrolein were tested in vivo by i.v. injection in rabbits (3, 4.5 and 6 mg/kg) and by injection into the yolk sac of rabbits embryos (10, 20 and 40 microliter/blastoderm of an 0.84% acrolein solution: yolk-sac method). After i.v. injection acrolein caused mainly embryolethal effects in a dose-dependent manner. After direct injection into the rabbit embryos acrolein led to an increase of resorption and malformation rate in a dose-dependent manner. The highest dose in both investigations showed that by i.v. injection acrolein acts as an embryotoxic agent in a 50-60 times lower concentration. As acrolein plays an important role in the metabolism of cyclophosphamide the results are discussed in relation to the embryotoxicity of cyclophosphamide.

Abnormalities, Drug-Induced↗
PubMed1995

Inactivation of DNA polymerase alpha-primase by acrolein: loss of activity depends on the DNA substrate.

We have utilized acrolein as a model compound to examine the biochemical behavior of chemically-modified DNA polymerase alpha-primase complex (pol alpha). We have found that acrolein irreversibly inactivates the DNA synthetic capacity of pol alpha polymerase in a time- and concentration-dependent manner. Double-stranded DNA protects pol alpha polymerase from inactivation when present during acrolein exposure, but single-stranded DNA, dATP and ATP do not. Strikingly, the activity of pol alpha polymerase is strongly dependent upon the DNA substrate utilized to assay catalytic activity after exposure to the aldehyde. The primase activity of pol alpha is also inactivated by exposure to acrolein, but the observed rate of inactivation is slower than that seen for DNA synthesis. Competitive labeling studies with [14C] iodoacetamide suggest that acrolein inactivation of the enzyme is mediated through the modification of protein sulfhydryl groups.

Acrolein↗
PubMed2004

Detection of acrolein-lysine adducts in plasma low-density lipoprotein and in aorta of cyclophosphamide-administered rats.

Cyclophosphamide (CY) is an alkylating agent used for the treatment of various types of cancer and is also used as a potent immunosuppressant. Acrolein, a metabolite of CY is cytotoxic and has the ability to covalently bind with proteins in vitro to form acrolein-protein adducts. These protein adducts are considered to be putative markers of oxidative stress and cause damage to protein in aging, atherosclerosis and diabetes. We have, for the first time, detected acrolein-lysine adducts in plasma low-density lipoprotein (LDL) and in the aorta of CY-treated animals by agarose gel electrophoresis, immunoblot and immunohistochemical methods. The extent of lipid peroxidation caused by the metabolite acrolein in plasma LDL was also measured quantitatively by using high-performance liquid chromatography. These results confirm the role of acrolein-lysine adducts in the development of atherosclerosis or atherogenesis.

Acrolein↗
PubMed2005

Accumulation of acrolein-protein adducts after traumatic spinal cord injury.

Reactive oxygen species and resultant lipid peroxidation (LPO) have been associated with central nervous system trauma. Acrolein (2-propenal) and 4-hydroxynonenal (HNE) are the most toxic byproducts of LPO, with detrimental effects in various types of cells. In this study, we used immunoblotting techniques to detect the accumulation of protein-bound acrolein and HNE. We report that protein-bound acrolein and HNE were significantly increased in guinea pig spinal cord following a controlled compression injury. The acrolein and HNE protein-adducts increased in the damaged spinal cord as early as 4 h after injury, reached a peak at 24 h after injury, and remained at a significantly high level up to 7 days after injury. Such increase of protein adducts was also observed in the adjacent segments of the injury site beginning at 24 h post injury. These results suggest that products of lipid peroxidation, especially acrolein, may play a critical role in the secondary neuronal degeneration, which follows mechanical insults.

Acrolein↗
PubMed1982

Allylamine cardiotoxicity--IV. Metabolism to acrolein by cardiovascular tissues.

Acrolein was detected in homogenates of rat aorta, lung, skeletal muscle, and heart incubated with allylamine. Semicarbazide and hydralazine, which protect against allylamine-induced myocardial injury in vivo in the rat, inhibited acrolein formation. Hydrogen peroxide, a product of oxidative deamination, was generated during allylamine oxidation. Acrolein was also produced from allylamine by bovine plasma amine oxidase and porcine kidney diamine oxidase but not by rat liver or brain homogenates. Allylamine competitively inhibited benzylamine oxidation in rat aorta, but pargyline-sensitive monoamine oxidase was not involved in acrolein production. The high activity in aorta, the competition with benzylamine, and the sensitivity to benzylamine oxidase inhibitors indicate that benzylamine oxidase is the active enzyme in oxidizing allylamine. The formation of acrolein may be the basis of the cardiotoxic action of allylamine.

Acrolein↗
PubMed1990

Effects of acrolein on human platelet aggregation.

Acrolein, a component of tobacco smoke, potentiated platelet aggregation and increased thromboxane A2 (TXA2) formation caused by thrombin and arachidonic acid (AA). Acrolein produced these effects at concentrations in the range 50-5000 microM. Acrolein had no effect on platelet responses to ADP, epinephrine, collagen or the ionophore A23187. Acrolein increased the mobilization of [3H]arachidonic acid from prelabelled platelets in response to thrombin and arachidonic acid. The increased availability of substrate could partly explain the enhanced production of TXA2 and increased aggregation observed in the presence of acrolein. These findings could provide an explanation for the increased incidence of vascular disease in cigarette smokers.

Acrolein↗
PubMed1993

Effect of in vitro exposure to acrolein on carbachol responses in rat trachealis muscle.

Isolated tracheal rings obtained from male Wistar rats 10 to 15 weeks old and weighing 300 to 400 g were exposed to aqueous solutions of acrolein, and the resulting change of smooth muscle contractility was evaluated by measuring the cumulative carbachol concentration-response curve. Using the product of acrolein concentration and time as a surrogate for the acrolein dose delivered to the smooth muscle cells, contractility measured after a variety of exposure concentrations from 0.01 to 3.0 microM and times from 5 to 60 min could be correlated in a dose-dependent manner. In the range of doses from 0.1 to 6 microM-min, relative contractility continuously increased from 0 to 50% above unexposed control values. At doses greater than 6 microM-min, the enhancement in contractility declined. This decline may have been due to cell damage or cell death which was so severe at a dose of 60 microM-min that contractility fell below control values. Below a threshold dose of 0.1 microM-min, acrolein had no effect on contractility. The role arachidonic acid metabolism in the enhancement of smooth muscle reactivity to carbachol was studied using indometacin to block the cyclo-oxygenase pathway and NDGA to block the lipoxygenase pathway. At a concentration of 10 microM of either indometacin or NDGA, the acrolein-induced enhancement in airway reactivity was completely inhibited. At lower concentrations, inhibition by these two chemicals was partially additive, suggesting that both the lipoxygenase and cyclo-oxygenase pathways play a role in the hyperreactive response.

Acrolein↗
PubMed1991

Allylamine and acrolein toxicity in perfused rat hearts.

We assessed the in vitro toxicity of the cardiovascular toxicant allylamine, and its presumed in vivo metabolite, acrolein. In dose-response experiments, rat hearts perfused with allylamine (10-30 mM) or acrolein (0.01-3.0 mM) for 2 hr were assessed by standard histopathology and assay of creatine kinase (CK) in effluent. Allylamine-perfused hearts showed no grossly apparent functional abnormality except at 30 mM, but acrolein-perfused hearts beat irregularly and stopped rapidly (within 15 min at 0.01-0.3 mM, and by 5 min at 3.0 mM). Extensive contraction band necrosis and an apparently dose-dependent loss of CK were evident in allylamine-perfused hearts, whereas acrolein perfusion resulted in no morphologic lesions or CK loss. Additional experiments, however, suggest that acrolein perfusion results in denaturation of CK, making it undetectable in effluent. In hemodynamic preparations of rat hearts perfused with 10 mM allylamine, contraction band necrosis and extensive mitochondrial changes were seen by electron microscopy. Allylamine caused a marked rise in left ventricular pressure at 5 and 10 min, followed by a slow decline to a markedly depressed level at the end of 2 hr. End diastolic pressure rose steadily throughout the 2-hr perfusion. Coronary flow was similar in control and allylamine-perfused hearts for 1 hr, but then declined slowly. These experiments suggest that vascular spasm or alterations in coronary flow are not the cause of allylamine-induced myocardial damage. Allylamine's toxic effect on myocardium in this model may be mediated through its metabolism and subsequent injurious intracellular events.

Acrolein↗
PubMedDate not supplied

Mutagenesis of xeroderma pigmentosum fibroblasts by acrolein.

Acrolein, a short-chain aldehyde encountered as a component of tobacco smoke and as a ubiquitous environmental contaminant, was tested for its toxic and mutagenic effects toward human fibroblast cells. We found that human cells characterized by a deficiency in DNA repair (cells from xeroderma pigmentosum (XP) patients) were much more sensitive (D37 approximately equal to 0.25 microM) to the cytotoxic effects of acrolein than were cells from normal individuals (D37 approximately equal to 0.8 microM). Acrolein was also strongly mutagenic to the XP cells (a dose response was observed between 0.2 and 0.8 microM acrolein); however acrolein did not induce an increase in the mutant frequency of normal fibroblasts. Possible reasons for this apparent lack of mutagenicity in normal human cells are discussed.

Acrolein↗
PubMed1987

The pathologic and immunologic effects of inhaled acrolein in rats.

Four groups of 40 male Sprague-Dawley rats each were exposed by inhalation to target concentrations of 0, 0.1, 1.0, and 3.0 ppm of acrolein 6 h/day, 5 days/week for 3 weeks. Subsequent changes in local pulmonary immunity were determined by examining the number of antibody plaque-forming cells in the lung-associated lymph nodes following intratracheal immunization with sheep red blood cells. Separate groups of rats were evaluated for blastogenic responsiveness to phytohemagglutinin-P and Salmonella typhimurium antigen using spleen- and lung-associated lymph node cells. In vivo resistance was evaluated utilizing acrolein-exposed rats subsequently challenged with intravenous Listeria monocytogenes. Local pulmonary antibody responsiveness was not affected by acrolein exposure. Lymphocyte blastogenesis and resistance to Listeria challenge were not altered. Body weights and spleen weights were decreased in the 3 ppm-exposed group only. Microscopic examination of the nasal turbinates revealed acrolein-induced exfoliation, erosion, and necrosis of the respiratory epithelium as well as squamous metaplasia, however, lung histology was not affected. Thus at environmental concentrations, acrolein toxicity appeared to be confined to local nasal pathologic changes with no alterations in lung histology or immune function.

Acrolein↗
PubMed2005

Induction of thioredoxin reductase as an adaptive response to acrolein in human umbilical vein endothelial cells.

Acrolein is a highly electrophilic alpha,beta-unsaturated aldehyde to which humans are exposed in a variety of environment situations and is also a product of lipid peroxidation. Increased unsaturated aldehyde levels and reduced antioxidant status play an important role in the pathogenesis of a number of human diseases such as Alzheimer's, atherosclerosis, and diabetes. Mammalian thioredoxin reductase (TR), a central antioxidant enzyme, is a selenoprotein that catalyzes the reduction of oxidized thioredoxin. The findings reported here show that low concentrations of acrolein rapidly inactivate TR, both in vitro and in vivo. These data suggest that acrolein may directly inactivate TR, resulting in an increase in oxidative cellular damage. In addition, we also found that the initial inactivation of TR molecules by acrolein triggers a compensatory signal for inducing TR gene expression in human umbilical vein endothelial cells (HUVEC). The results of the present study suggest that HUVEC may have a protective system against cell damage by acrolein via the upregulation of TR, which is an adaptive response to oxidative stress.

Acetylcysteine↗
PubMed2006

Acrolein generation stimulates hypercontraction in isolated human blood vessels.

Increased risk of vasospasm, a spontaneous hyperconstriction, is associated with atherosclerosis, cigarette smoking, and hypertension-all conditions involving oxidative stress, lipid peroxidation, and inflammation. To test the role of the lipid peroxidation- and inflammation-derived aldehyde, acrolein, in human vasospasm, we developed an ex vivo model using human coronary artery bypass graft (CABG) blood vessels and a demonstrated acrolein precursor, allylamine. Allylamine induces hypercontraction in isolated rat coronary artery in a semicarbazide-sensitive amine oxidase activity (SSAO) dependent manner. Isolated human CABG blood vessels (internal mammary artery, radial artery, saphenous vein) were used to determine: (1) vessel responses and sensitivity to acrolein, allylamine, and H(2)O(2) exposure (1 microM-1 mM), (2) SSAO dependence of allylamine-induced effects using SSAO inhibitors (semicarbazide, 1 mM; MDL 72274-E, active isomer; MDL 72274-Z, inactive isomer; 100 microM), (3) the vasoactive effects of two other SSAO amine substrates, benzylamine and methylamine, and (4) the contribution of extracellular Ca(2+) to hypercontraction. Acrolein or allylamine but not H(2)O(2), benzylamine, or methylamine stimulated spontaneous and pharmacologically intractable hypercontraction in CABG blood vessels that was similar to clinical vasospasm. Allylamine-induced hypercontraction and blood vessel SSAO activity were abolished by pretreatment with semicarbazide or MDL 72274-E but not by MDL 72274-Z. Allylamine-induced hypercontraction also was significantly attenuated in Ca(2+)-free buffer. In isolated aorta of spontaneously hypertensive rat, allylamine-induced an SSAO-dependent contraction and enhanced norepinephrine sensitivity but not in Sprague-Dawley rat aorta. We conclude that acrolein generation in the blood vessel wall increases human susceptibility to vasospasm, an event that is enhanced in hypertension.

Acrolein↗
PubMed2003

Increase in putrescine, amine oxidase, and acrolein in plasma of renal failure patients.

Since polyamines have been suggested to be one of the uremic "toxins," the levels of each polyamine, its oxidized product, acrolein, and amine oxidase in plasma of patients with renal failure were investigated. The level of putrescine was increased, whereas the level of spermine was decreased in the plasma of patients with renal failure. The patients also had increased serum amine oxidase activity leading to increased degradation of spermine. Both levels of free and protein-conjugated acrolein were also increased in plasma of patients with renal failure. The accumulated acrolein found as protein conjugates was equivalent to 180 microM, which was 6-fold higher than in plasma of normal subjects. It was found that acrolein is mainly produced by polyamine oxidase in plasma. A cell lysate containing polyamine oxidase was cytotoxic in the presence of spermine. Our results indicate that the level of acrolein is well correlated with the degree of seriousness of chronic renal failure.

3T3 Cells↗
PubMed2002

Acrolein-induced cell death: a caspase-influenced decision between apoptosis and oncosis/necrosis.

Due to the dominating roles that caspases play in the apoptotic cascade, their activities appear to be a primary factor in the death pathway (apoptosis versus oncosis/necrosis) decision. In murine FL5.12 proB lymphocytes, the cellular consequences of acrolein treatment included a lack of typical apoptotic features in preference to oncosis/necrosis. Oncosis/necrosis was apparent by detection of a reduction in intracellular ATP concentration, increased plasma membrane leakage (measured by LDH release and flow cytometric detection of propidium iodide uptake) and morphological criteria. Analysis of acrolein-treated cell lysates or recombinant caspase enzymes showed overall dose-dependent decreases in caspase-3, -8 and -9 activities. In addition to acrolein's effect on intracellular caspases, it was also able to alter caspase-dependent apoptosis induced by secondary treatment with etoposide or following cytokine withdrawal. Acrolein at doses > or =20 microM circumvented etoposide or interleukin-3 withdrawal induced apoptosis. When acrolein was combined with mechlorethamine, another alkylating agent not dependent on caspases for its cell death signaling, necrosis was increased in a dose-dependent manner. Overall, these data suggest that caspase inhibition plays an important role in the cell death pathway decision, particularly with treatments dependent on the caspase cascade to induce apoptosis.

Acrolein↗
PubMedDate not supplied

Acrolein is increased in Alzheimer's disease brain and is toxic to primary hippocampal cultures.

Accumulating evidence implicates oxidative stress in the pathogenesis of several neurodegenerative diseases including Alzheimer's disease (AD). Increased lipid peroxidation, decreased levels of polyunsaturated fatty acids, and increased levels of 4-hydroxynonenal (HNE), F(2)-isoprostanes, and F(4)-neuroprostanes are present in the brain in AD. Acrolein, an alpha,beta-unsaturated aldehydic product of lipid peroxidation, is approximately 100 times more reactive than HNE and recently was demonstrated in neurofibrillary tangles in the brain in AD. In three brain regions of 10 AD patients compared with 8 age-matched control subjects, we found increased mean extractable acrolein, with the increases reaching statistical significance in the amygdala and hippocampus/parahippocampal gyrus. In hippocampal neuron cultures, acrolein was neurotoxic in a time- and concentration-dependent manner and more toxic than HNE at 5 microM concentrations of each. Acrolein exposure led to a significant concentration-dependent increase in intracellular calcium concentrations. Collectively, these data show that acrolein is increased in the brain in AD and demonstrate neurotoxicity mechanisms that might be important in the pathogenesis of neuron degeneration in AD.

Acrolein↗
PubMed2002

Acrolein inflicts axonal membrane disruption and conduction loss in isolated guinea-pig spinal cord.

We have examined the effect of acrolein, an aldehyde product of lipid peroxidation, on axons in isolated guinea-pig spinal cord white matter. We found that 200 microM acrolein, but not 50 microM, induced a time-dependent loss of compound action potential conduction. Such conduction loss was irreversible within 1 h after acrolein perfusion. Parallel anatomical assessment indicates membrane integrity breakdown based on a horseradish peroxidase-exclusion assay. This is the first report to suggest that acrolein inflicts severe axonal damage. Since axonal damage within white matter plays a key role in the pathology of traumatic spinal cord injury, we suggest that acrolein may be a critical factor in mediating secondary functional loss.

Acrolein↗
PubMed2001

Acrolein inhibits respiration in isolated brain mitochondria.

Lipid peroxidation is elevated in diseased regions of brain in several neurodegenerative diseases. Acrolein (2-propenal) is a major cytotoxic product of lipid peroxidation and its adduction to neuronal proteins has been demonstrated in diseased brain regions from patients with Alzheimer's disease. Mitochondrial abnormalities are implicated in several neurodegenerative disorders, and mitochondria are targets of alkenal adduction in vivo. We examined the effects of acrolein upon multiple endpoints associated with the mitochondrial involvement in neurodegenerative disease. Acrolein inhibited state 3 respiration with an IC(50) of approx. 0.4 micromol/mg protein; however, there was no reduction in activity of complexes I-V. This inhibition was prevented by glutathione and N-acetylcysteine. Acrolein did not alter mitochondrial calcium transporter activity or induce cytochrome c release. These studies indicate that acrolein is a potent inhibitor of brain mitochondrial respiration.

Acrolein↗
PubMed2006

A sensitive method for the quantification of acrolein and other volatile carbonyls in ambient air.

Acrolein, an unsaturated aldehyde found in both indoor and outdoor air, is considered one of the greatest noncancer health risks of all organic air pollutants. Current methods for determining acrolein often employ sorbent-filled cartridges containing a carbonyl derivatizing agent (e.g., dinitrophenylhydrazine). These methods are of limited use for unsaturated compounds due to the formation of unstable derivatives, coelution of similar compounds, long sample collection times, and ozone interferences that result in poor sensitivity, selectivity, and reproducibility. The goal of this research was to develop an analytical method for determining ppt concentrations of acrolein and other carbonyls in air with short sampling times (10 min). The method uses a mist chamber to collect carbonyls by forming water-soluble carbonyl-bisulfite adducts. The carbonyls are then liberated from the bisulfite, derivatized, and quantified by gas chromatography/electron capture negative ionization mass spectrometry. The method was applied to determine atmospheric acrolein concentrations at three sites in northern California reflecting hemispheric background concentrations, biogenic-dominated regions, and urban environments. The resulting acrolein concentrations were 0.056, 0.089, and 0.29 microg/m3, respectively, which are all above the EPA Reference Concentration of 0.02 microg/m3. The minimum detection limit of 0.012 microg/m3 is below that of other published methods. Methacrolein, methyl vinyl ketone, crotonaldehyde, glyoxal, methyl glyoxal, and benzaldehyde were also quantified.

Acrolein↗