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PubMed1982

Acrolein: a potent modulator of lung macrophage arachidonic acid metabolism.

Resting rat pulmonary alveolar macrophages exposed to acrolein were stimulated to synthesize and release thromboxane B2 and prostaglandin E2 in a dose-dependent manner. Zymosan-activated pulmonary alveolar macrophages released approximately twice as much prostaglandin E2 as thromboxane B2, whereas acrolein-activated pulmonary alveolar macrophages released 4-5 times less prostaglandin E2 than thromboxane B2. In the zymosan-stimulated pulmonary alveolar macrophages, acrolein also induced a reversal in the relative amounts of prostaglandin E2 and thromboxane B2 synthesized and released into the culture medium. This reversal was achieved by a dose-dependent reduction in prostaglandin E2 synthesis. Although phagocytosis was also inhibited in a dose-dependent manner, the reduction in prostaglandin E2 appeared to be partially independent of particle ingestion since thromboxane B2 synthesis was not affected by low doses of acrolein. In fact, high doses induced a slight enhancement in thromboxane B2 synthesis. These results suggest that acrolein selectively inhibited the enzyme, prostaglandin endoperoxide E isomerase, necessary for the conversion of the endoperoxide to prostaglandin E2. Sulfhydryl reagents such as N-ethylmaleimide and 5,5'-dithiobis (2-nitrobenzoic acid) mimicked acrolein's effects, and reduced glutathione afforded protection against the effects of acrolein. These results indicated the possible involvement of acrolein's sulfhydryl reactivity in the inhibition of the isomerase enzyme. Propionaldehyde had no effect on macrophage arachidonic acid metabolism whereas crotonaldehyde mimicked the effects of acrolein. Pulmonary macrophages were unable to reverse the acrolein effects on arachidonate metabolite synthesis after 6 h in an acrolein-free environment. These data indicated the necessity of the unsaturated carbon bond for the acrolein effects on arachidonic acid metabolism and the relative irreversibility of acrolein's reaction with the macrophage.

Acrolein↗
PubMed2006

P38 and ERK mitogen-activated protein kinases mediate acrolein-induced apoptosis in Chinese hamster ovary cells.

Acrolein, which is a highly reactive alpha,beta-unsaturated aldehyde generated by lipid peroxidation, can affect cells and tissues and cause various disorders. Increased levels of unsaturated aldehydes play an important role in the pathogenesis of a number of human diseases such as Alzheimer's disease, atherosclerosis and diabetes. Acrolein is a highly ubiquitous toxic environmental pollutant. Because of human exposure, there is a need for investigating the mechanisms involved in acrolein toxicity at the cellular and molecular levels. Acrolein can induce cell death by apoptosis, although the mechanisms are not entirely clear. The present study investigates whether mitogen-activated protein kinases (MAPKs) play a role in activation of apoptosis by acrolein. Our findings show that acrolein-mediated apoptosis is in fact MAPK-dependent in Chinese hamster ovary cells. The MAP family kinases, including ERK and p38 kinase, and the transcription factor c-Jun were all activated by phosphorylation after 1 h exposure to acrolein. Phosphorylation of ERK and p38 kinases and their blockade by an ERK inhibitor, U0126, or a p38 inhibitor, SB203580, respectively, suggested that activation of apoptosis by acrolein is ERK- and p38-dependent. Thus, blockade of ERK and p38 inhibited chromatin condensation, caspase-7 and -9 activation as well as ICAD cleavage induced by acrolein. JNK and AKT kinases seem to be implicated in survival pathways against acrolein insult, since their respective inhibitors, SP600125 and LY294002/Wortmannin switched the mode of cell death from apoptosis to total necrosis. Finally, acrolein induced phosphorylation of the pro-apoptotic factor p53 which is responsible for transcription of pro-apoptotic factors such as Bax and Fas ligand. These results provide new information demonstrating the implication of MAPKs and AKT in acrolein-induced apoptosis, and this information may be useful for understanding the pathogenesis of a number of tissue diseases and environmental toxicity in response to acrolein.

Acrolein↗
PubMed2006

Upregulation of endothelial heme oxygenase-1 expression through the activation of the JNK pathway by sublethal concentrations of acrolein.

Acrolein is a highly electrophilic alpha,beta-unsaturated aldehyde that is present in cigarette smoke. Heme oxygenase-1 (HO-1) is a cytoprotective enzyme activated by various such electrophilic compounds. In this study, the regulatory effects of acrolein upon the expression of HO-1 were investigated in endothelial cells (ECs). We demonstrate that acrolein induces the elevation of HO-1 protein levels, and subsequent enzyme activity, at non-cytotoxic concentrations. An additional alpha,beta-unsaturated aldehyde, cinnamaldehyde, was also found to increase HO-1 expression and have less cytotoxicity than acrolein. Moreover, acrolein-mediated HO-1 induction is abrogated in the presence of actinomycin D and cycloheximide. Nrf2 is a transcription factor involved in the induction of HO-1 through an antioxidant response element (ARE) in the promoter region of the HO-1 gene. We show that acrolein induces Nrf2 translocation and ARE-luciferase reporter activity. Acrolein was also found to induce the production of both superoxide and H2O2 at levels greater than 100 microM. However, with the exception of NAC, no antioxidant generated any effect upon acrolein-dependent HO-1 expression in ECs. Our present findings suggest that reactive oxygen species (ROS) may not be a major modulator for HO-1 induction. Using buthionine sulfoximine to deplete the intracellular GSH levels further enhanced the effects of acrolein. We also found that cellular GSH level was rapidly reduced after both 10 and 100 microM acrolein treatment. However, after 6 h of exposure to ECs, only 10 microM acrolein treatment increases GSH level. In addition, only the JNK inhibitor SP600125 and tyrosine kinase inhibitor genistein had any significant inhibitory impact upon the upregulation of HO-1 by acrolein. Pretreatment with a range of other PI3 kinase inhibitors, including wortmannin and LY294002, showed no effects. Hence, we show in our current experiments that a sublethal concentration of acrolein is in fact a novel HO-1 inducer, and we further identify the principal underlying mechanisms involved in this process.

Acrolein↗
PubMed2003

Modulation of benzo[a]pyrene-induced p53 DNA activity by acrolein.

Acrolein, a highly electrophilic alpha,beta-unsaturated aldehyde, is by far the most reactive amongst the aldehydes present in smoke. The relative contribution of acrolein to complex mixture toxicity of smoke at the molecular level remains unknown. The current study examines the ability of acrolein to modulate the effect of benzo[a]pyrene (B[a]P), a major carcinogen found in smoke, on p53. Exposure of human lung adenocarcinoma A549 cells to 1 mM B[a]P for 48 h strongly activated the expression of p53 as seen by western blotting, and its DNA binding as shown by an electrophoretic mobility shift assay. Treatment of A549 cells with a non-lethal dose of acrolein alone (50 fmol/cell for 0.5 h) depleted 80% of total cellular glutathione but had no effect on basal p53 protein levels. When B[a]P-treated cells (48 h) were exposed to acrolein for 0.5 h there was also no effect on B[a]P-induced p53 protein levels. However, acrolein treatments profoundly inhibited the DNA binding of p53 under both basal and B[a]P-induced conditions. Depleting glutathione with buthionine sulfoximine in B[a]P-treated cells to levels similar to those obtained with acrolein decreased p53 DNA binding substantially less than with acrolein. Using a p53 dual luciferase reporter assay, acrolein caused an 83% decrease in the p53 activity induced by B[a]P (1 mM for 24 h post-transfection). The p53 protein that was immunoprecipitated after acrolein treatment was reactive with an anti-acrolein antibody indicating covalent modification. Results from this study suggest that acrolein can inhibit p53 DNA binding and activity by direct covalent modification as well as alteration of intracellular redox status. As both acrolein and B[a]P are found in cigarette smoke, this type of interaction may play an important role in the initiation of lung cancer by altering the tumor suppressor activity of p53.

Acrolein↗
PubMed2006

Acrolein induces vasodilatation of rodent mesenteric bed via an EDHF-dependent mechanism.

Acrolein is generated endogenously during lipid peroxidation and inflammation and is an environmental pollutant. Protein adducts of acrolein are detected in atherosclerotic plaques and neurons of patients with Alzheimer's disease. To understand vascular effects of acrolein exposure, we studied acrolein vasoreactivity in perfused rodent mesenteric bed. Acrolein induced endothelium-dependent vasodilatation that was more robust and more sensitive than dilation induced by 4-hydroxy-trans-2-nonenal, trans-2-hexenal, or propionaldehyde. Acrolein-induced vasodilatation was mediated by K(+)-sensitive components, e.g., it was abolished in 0 [K(+)](o) buffer or in 3 mM tetrabutylammonium, inhibited 75% in 50 microM ouabain, and inhibited 64% in 20 mM K(+) buffer. Moreover, combined treatment with the Ca(2+)-activated K(+) channel inhibitors 1-[(2-chlorophenyl)diphenylmethyl]-1H-pyrazole (TRAM-34, 100 nM) and apamin (5 microM) significantly reduced vasodilatation without altering sensitivity to acrolein. However, acrolein-induced % dilation was unaffected by l-NAME or indomethacin pretreatment indicating mechanistic independence of NO and prostaglandins. Moreover, acrolein induced vasodilatation in cirazoline-precontracted mesenteric bed of eNOS-null mice confirming eNOS independence. Pretreatment with 6-(2-propargyloxyphenyl) hexanoic acid (PPOH 50 microM), an epoxygenase inhibitor, or the superoxide dismutase mimetic Tempol (100 microM) significantly attenuated acrolein-induced vasodilatation. Collectively, these data indicate that acrolein stimulates mesenteric bed vasodilatation due to endothelium-derived signal(s) that is K(+)-, ouabain-, PPOH-, and Tempol-sensitive, and thus, a likely endothelium-derived hyperpolarizing factor (EDHF). These data indicate that low level acrolein exposure associated with vascular oxidative stress or inflammation stimulates vasodilatation via EDHF release in medium-sized arteries--a novel function.

Acrolein↗
PubMed2003

Acrolein-induced vasomotor responses of rat aorta.

Acrolein is a highly reactive aldehyde pollutant and an endogenous product of lipid peroxidation. Increased generation of, or exposures to, acrolein incites pulmonary and vascular injury. The effects of acrolein on the vasomotor responses of rat aortic rings were studied to understand its mechanism of action. Incubation with acrolein (10-100 microM) alone did not affect the resting tone of aortic vessels; however, a dose-dependent relaxation of phenylephrine-precontracted aortic rings was observed. Acrolein-induced relaxation was slow and time dependent and the extent of relaxation after 100 min of application was 44.7 +/- 4.1% (10 microM), 56.0 +/- 5.6% (20 microM), 61.0 +/- 7.9% (40 microM), and 96.1 +/- 2.1 (80 microM), respectively, versus 14.2 +/- 3.3% relaxation in the absence of acrolein. Acrolein-induced vasorelaxation was prevented by endothelial denudation and was abolished on pretreatment with the nitric oxide synthase inhibitor Nomega-nitro-L-arginine methyl ester, the guanylyl cyclase inhibitor 1H-[1,2,4]oxidazolo[4,3-a]quinoxaline-1-one, or the cyclooxygenase inhibitor indomethacin. Inhibition of K+ channels (by tetrabutylammonium) or Na+-K+-ATPase (by ouabain) did not significantly prevent acrolein-mediated vasorelaxation. Exposure to acrolein in the presence or absence of other compounds elicited slow wave vasomotor effect in 77% of aortic vessels versus 1.4% in control. Vasomotor responses were also studied on aortic rings prepared from rats fed 2 mg. kg-1. day-1 acrolein for 3 alternate days by oral gavage. These vessels developed a significantly lower contractile response to phenylephrine compared with controls. Together, these results indicate that acute acrolein exposure evokes delayed vasorelaxation due to a nitric oxide- and prostacyclin-dependent mechanism, whereas in vivo acrolein exposure compromises vessel contractility.

Acrolein↗
PubMed1998

Calcium signaling in airway smooth muscle cells is altered by in vitro exposure to the aldehyde acrolein.

We have previously observed that acrolein administered ex vivo to isolated airways alters the subsequent airway responsiveness. To examine the cellular mechanisms involved in this alteration, we have studied the effect of acrolein exposure on calcium signaling in myocytes freshly isolated from rat trachea. We have also studied the effect of acrolein exposure on isometric contraction of rat epithelium-free tracheal rings. Tissues were exposed to a variety of acrolein concentrations from 0.1 to 1 microM and durations from 5 to 15 min. In isolated cells, exposure to acrolein did not modify the resting cytosolic Ca2+ concentration ([Ca2+]i) whatever the concentration or duration of exposure, but altered the pattern of the Ca2+ response to acetylcholine (ACh). ACh typically induces an initial [Ca2+]i rise followed by peaks of decreasing amplitude (oscillations). Exposure to a fixed concentration of acrolein (0.2 microM) for 5 and 10 min significantly enhanced the amplitude of the initial [Ca2+]i rise in response to a low concentration of ACh (0.1 microM) by 50.8 and 77%, respectively. Similarly, exposure for a fixed duration of 10 min significantly enhanced the amplitude of the initial [Ca2+]i rise by 49.4% at an acrolein concentration of 0.3 microM. When cells were stimulated with a high ACh concentration (10 microM), the value of the first [Ca2+]i peak was not changed by acrolein exposure; but the frequency at which subsequent peaks occurred was significantly increased by 44.4% after 10 min of exposure to a fixed concentration of 0.2 microM and by 36.3% following an exposure for a fixed duration of 10 min at the concentration of 0.3 microM. In contrast, acrolein, whatever the concentration, had no effect on the caffeine-induced [Ca2+]i response. In rat epithelium-free tracheal rings, acrolein increased the response to muscarinic stimulation, with a maximal effect observed for an exposure to 0.3 microM for 10 min. The effect of acrolein on the [Ca2+]i response of isolated myocytes occurred over a range of doses similar to that on the contractile response of rings, suggesting that the effect of this pollutant on calcium signaling may account, at least partially, for acrolein-induced airway hyperresponsiveness.

Acetylcholine↗
PubMed2006

A model of hemorrhagic cystitis induced with acrolein in mice.

Acrolein is a urinary metabolite of cyclophosphamide and ifosfamide, which has been reported to be the causative agent of hemorrhagic cystitis induced by these compounds. A direct cytotoxic effect of acrolein, however, has not yet been demonstrated. In the present study, the effects of intravesical injection of acrolein and mesna, the classical acrolein chemical inhibitor, were evaluated. Male Swiss mice weighing 25 to 35 g (N = 6 per group) received saline or acrolein (25, 75, 225 microg) intravesically 3, 6, 12, and 24 h before sacrifice for evaluation of bladder wet weight, macroscopic and histopathological changes by Gray's criteria, and 3 and 24 h for assessment of increase in vascular permeability. In other animals, mesna was administered intravesically (2 mg) or systemically (80 mg/kg) 1 h before acrolein. Intravesical administration of acrolein induced a dose- and time-dependent increase in vascular permeability and bladder wet weight (within 3 h: 2.2- and 21-fold increases in bladder wet weight and Evans blue dye exuded, respectively, at doses of 75 microg/bladder), as confirmed by Gray's criteria. Pretreatment with mesna (2-mercaptoethanesulfonic acid), which interacts with acrolein resulting in an inactive compound, inhibited all changes induced by acrolein. Our results are the first demonstration that intravesical administration of acrolein induces hemorrhagic cystitis. This model of acrolein-induced hemorrhagic cystitis in mice may be an important tool for the evaluation of the mechanism by which acrolein induces bladder lesion, as well as for investigation of new uroprotective drugs.

Acrolein↗
PubMed2005

Influence of protein binding on acrolein turnover in vitro by oxazaphosphorines and liver microsomes.

For a correct determination of acrolein amounts generated in in vitro turnover experiments with oxazaphosphorines, it is necessary to characterize the interaction of acrolein with liver microsomal proteins. Acrolein, a highly reactive metabolite of oxazaphosphorines, readily forms covalent adducts with proteins by electrophilic attack on nucleophiles, such as the sulfhydryl group of cysteine, imidazole group of histidine, and amino group of lysine. The current investigations were mainly directed toward determination of the degree of acrolein-protein binding under conditions of in vitro experiments with liver microsome preparations. The acrolein concentration in protein dilution was determined by a fluorescence method. Moreover, the influence of sucrose and glycerine on the extent of acrolein-protein binding commonly used for the stabilization of microsomal preparations during storage was investigated. The current investigations show evidence that the chemical reaction of acrolein with liver microsomal proteins strictly follows first order kinetics. The main part of the formed acrolein in the in vitro attempts is available as bound part. Results of these investigations indicate that the calibration should be carried out with mixtures from liver microsome preparations and known amounts of acrolein under the same conditions as the in vitro experiments to record the entirely formed acrolein part (free and bound) in oxazaphosphorine turnover experiments. Glycerine is recommended as a preservative to store liver microsomes instead of sucrose because the latter reacts with acrolein.

Acrolein↗
PubMed2000

Cellular mechanisms of acrolein-induced alteration in calcium signaling in airway smooth muscle.

Acrolein, an unsaturated aliphatic aldehyde, is a potent respiratory irritant. We have previously observed that acrolein administered ex vivo to isolated airways alters subsequent airway responsiveness to muscarinic agonists in terms of both mechanical activity of rings and calcium signaling in isolated cells. In the present study, we have examined the mechanisms by which acrolein alters Ca(2+) signaling. In freshly isolated rat tracheal smooth muscle cells, preexposure to acrolein increased the [Ca(2+)](i) oscillation frequency in response to endothelin 1 (ET-1, 0.1 microM), a contractile agonist that acts via the activation of a receptor different from the muscarinic cholinoceptor. We then studied acrolein-induced alteration in cell signaling with special attention to the steps downstream of membrane receptor activation i.e., the inositol 1,4,5-trisphosphate (InsP(3)) signaling pathway. Pretreatment of cells with LiCl (20 mM), a modulator of InsP(3) concentration, mimicked the effect of acrolein exposure on agonist-induced [Ca(2+)](i) response, i.e., increased the amplitude of the first Ca(2+) rise and the oscillation frequency in response to 0.1 and 10 microM acetylcholine (ACh), respectively. Moreover, in tracheal smooth muscle, preexposure to acrolein significantly increased carbachol-induced [(3)H]inositol-phosphates accumulation, up to 34 +/- 11% above unexposed tissue values. Finally, in beta-escin permeabilized cells, injection of InsP(3) (0.1-10 microM) induced a concentration-dependent [Ca(2+)](i) rise followed, for high InsP(3) concentration, by [Ca(2+)](i) oscillations, a calcium response whose pattern was similar to that induced by ACh. Exposure to acrolein did not alter the InsP(3)-induced [Ca(2+)](i) response. These results indicate that the effect of acrolein exposure on Ca(2+) responses in airway smooth muscle is not restricted to activation of the muscarinic cholinoceptor and is due to an enhancement in agonist-induced InsP(3) production. Since acrolein does not modify InsP(3) receptor channel sensitivity, we conclude that acrolein-induced alteration in calcium signaling can be ascribed to its sole effect on InsP(3) production.

Acrolein↗
PubMed1980

Does acrolein contribute to the cytotoxicity of cyclophosphamide?

To determine whether the release of acrolein from oxazaphosphorinane-cytostatics contributes to their cytotoxic action, the effect of 4-hydroperoxycyclophosphamide, 4-hydroperoxy-semi-cyclophosphamide, 4-hydroperoxy-dechloro-cyclophosphamide, and acrolein on murine L 1210 leukemia cells in vitro was compared by measuring the median survival time (MST) after transplantation of the tumor cells in DBA2/Han mice. We found that only 4-hydroperoxycyclophosphamide, which is able to release both acrolein and the alkylating metabolite phosphoramide-mustard, decreased the transplantability of L 1210 cells, while the structurally analogous 4-hydroperoxy-dechloro-cyclophosphamide and 4-hydroperoxy-semi-cyclophosphamide, which under physiological conditions only release acrolein but no alkylating split products showed no cytotoxicity. Acrolein itself showed only a marginal effect, when administered in concentrations equivalent to the release of acrolein from the oxazaphosphorinane-derivatives in test. In this case, however, significant lysis of the L 1210 cells was observed by estimating dye exclusion, while acrolein released intracellularly from 4-hydroperoxy-oxazaphosphorinane-compounds did not. This points to a different mechanism of the cytotoxic action of extracellular acrolein and acrolein released intracellularly from activated oxazaphosphorinane-compounds. The results suggest that the cytotoxic effect of activated cyclophosphamide is based on the alkylating moiety of the molecule. Neither the 4-hydroperoxy-group nor the activated oxazaphosphorinane-ring itself, nor acrolein released intracellularly during toxification of activated cyclophosphamide exert a direct cytotoxic effect. Thus, the release of acrolein from activated CP apparently does not contribute to the cytotoxicity of CP in vivo.

Acrolein↗
PubMed1987

Enhancement of the embryotoxicity of acrolein, but not phosphoramide mustard, by glutathione depletion in rat embryos in vitro.

The intracellular thiol glutathione is known to protect cells against the toxicity of certain drugs and reactive intermediates. In this study, the role of glutathione in protecting the embryo against two embryolethal and teratogenic metabolites of cyclophosphamide, and anticancer drug, was assessed in vitro using the rat whole embryo culture system. Day 10.5 rat embryos were cultured in rat serum medium containing phosphoramide mustard (1, 10, or 25 microM) or acrolein (10, 25, 50 or 100 microM), with and without buthionine sulfoximine (10 or 100 microM), a compound which depletes glutathione by inhibiting its synthesis. After 45 hr, embryos were assessed for viability, malformations, growth and development, and the glutathione content of embryos exposed to buthionine sulfoximine alone was assayed. The glutathione levels of the embryos and their yolk sacs were decreased significantly by 100 microM buthionine sulfoximine, whereas 10 microM buthionine sulfoximine decreased glutathione levels in the yolk sacs only. Phosphoramide mustard alone, at concentrations of 10 and 25 microM, did not produce embryo deaths but did cause malformations and growth retardation in 100% of the exposed embryos. The addition of buthionine sulfoximine (100 microM) had no effect on the teratogenicity or growth-retarding effects of phosphoramide mustard. Acrolein alone produced a 25 and 48% incidence of embryo deaths at 50 and 100 microM, respectively, and a 46% incidence of embryo malformations, as well as significant growth retardation, among the surviving embryos at 100 microM. Buthionine sulfoximine (10 or 100 microM) significantly enhanced the embryotoxic effects of acrolein. The addition of 10 microM buthionine sulfoximine resulted in 100% embryolethality at 100 microM acrolein; this buthionine sulfoximine concentration decreased the EC50 values for embryo deaths and malformations to 50% of those for acrolein alone. The addition of 100 microM butionine sulfoximine significantly potentiated the embryolethality of acrolein at 25, 50 and 100 microM; the combination of 100 microM acrolein plus 100 microM buthionine sulfoximine was 100% embryolethal. The incidence of embryo malformations was enhanced significantly at 10 and 25 microM acrolein by 100 microM buthionine sulfoximine. The EC50 values for embryo deaths and malformations were decreased to 50 and 20%, respectively, of those values for acrolein alone. Both butionine sulfoximine concentrations produced significant growth retardation at all acrolein concentrations compared to either acrolein or buthionine sulfoximine alone.(ABSTRACT TRUNCATED AT 400 WORDS)

Abnormalities, Drug-Induced↗
PubMed2006

Reduction of acrolein by elemental iron: kinetics, pH effect, and detoxification.

Acrolein is a highly toxic alpha,beta-unsaturated aldehyde that is widely used as a biocide, a cross-linking agent, and an intermediate in the chemical industry, among other applications. In this study we investigated the reductive transformation of acrolein by elemental iron and evaluated the feasibility of using iron to detoxify acrolein. At acidic and neutral pH, acrolein was transformed by iron through reduction of the C=C double bond to propionaldehyde. The reduction appeared to involve the chemisorption of acrolein to the iron surface followed by reduction of adsorbed acrolein. Both the adsorption and reduction rate constants decreased with increasing pH. Between pH 7.0 and 7.4, the acrolein adsorption rate constant decreased precipitously, resulting in a sharp decline in its removal rate. At higher pH, acrolein disappeared rapidly in control without iron, presumably due to reversible, base-catalyzed hydration. At equilibrium, approximately 93% of acrolein was hydrated, corresponding to an equilibrium constant of 13. Acrolein at 25 mg/L completely inhibited aerobic respiration; in contrast, its reduction product propionaldehyde was biodegradable. This suggests that elemental iron may be used to pretreat acrolein-containing wastes prior to aerobic biodegradation. To our knowledge, this is the first report of reduction and detoxification of an alpha,beta-unsaturated aldehyde by elemental iron.

Acrolein↗
PubMed1995

Acrolein mercapturates: synthesis, characterization, and assessment of their role in the bladder toxicity of cyclophosphamide.

Acrolein is the metabolite of cyclophosphamide (CP) believed to be involved in the bladder toxicity associated with this anticancer drug. The mechanism by which this extremely reactive intermediate is delivered to the bladder is not known. Glutathione (GSH) readily conjugates with acrolein, and the acrolein mercapturate S-(3-hydroxypropyl)-N-acetylcysteine (3-hydroxy-PrMCA) has been found in the urine of animals and man given CP. The objectives of this study were to prepare and characterize synthetic standards of the GSH acrolein adduct (3-oxopropyl)glutathione (3-oxoPrGSH), the acrolein mercapturates S-(3-oxopropyl)-N-acetylcysteine (3-oxoPrMCA) and 3-hydroxyPrMCA, and the S-oxidation product of 3-oxoPrMCA (3-oxoPrMCA S-oxide). In addition, the release of acrolein from, and the bladder toxicity of, these conjugates was determined. 3-OxoPrGSH and 3-oxoPrMCA were prepared with a 99% yield by condensing acrolein with GSH and N-acetylcysteine, respectively. 3-HydroxyPrMCA was prepared with a 63% yield by refluxing 3-chloropropanol and N-acetylcysteine in a basic medium. Oxidation of 3-oxoPrMCA with H2O2 was used to prepare 3-oxoPrMCA S-oxide. By decreasing the reaction time to 1 h, and adjusting the ratio of 3-oxoPrMCA to H2O2, the yield of 3-oxoPrMCA S-oxide was increased to 96%. The anhydrous aldehyde, 3-oxoPrMCA, afforded characteristic aldehydic proton resonances (1H NMR) in deuterated dimethyl sulfoxide. New resonances were observed in deuterated water, indicating a 75% hydration of the aldehyde to the corresponding geminal diol. This phenomenon was enhanced with 3-oxoPrMCA S-oxide where approximately 100% hydration of the aldehyde to the corresponding geminal diol was observed. When incubated at 25 degrees C in 100 mM potassium phosphate buffer containing 1 M KCl, pH 8.0, 3-oxoPrMCA released approximately 6% and 3-oxoPrMCA S-oxide released approximately 16-18% of the theoretical maximum yield of acrolein after 30 min, as indicated by an increase in absorbance at 210 nm and confirmed by trapping this aldehyde as a semicarbazone. There was less than a 2% yield of acrolein from 3-hydroxyPrMCA or 3-oxoPrGSH under similar conditions. At pH 7.4 the release of acrolein from 3-oxoPrMCA and 3-oxoPrMCA S-oxide was decreased by 50%. An assay where aldehydes are reacted with m-aminophenol in acid media produced fluorescence consistent with 72%, 46%, 23%, and 1% yields of acrolein from 3-oxoPrMCA S-oxide, 3-oxoPrMCA, 3-oxoPrGSH, and 3-hydroxyPrMCA, respectively.(ABSTRACT TRUNCATED AT 400 WORDS)

Acetylcysteine↗
PubMed2002

Inhibition of cell proliferation and AP-1 activity by acrolein in human A549 lung adenocarcinoma cells due to thiol imbalance and covalent modifications.

Acrolein, a reactive alpha,beta-unsaturated aldehyde, is a common environmental pollutant, a metabolite of the anticancer drug cyclophosphamide, and a byproduct of lipid peroxidation. An increase in acrolein production has been proposed as a marker for Alzheimer's disease, diabetic glomerular lesions, and atherosclerosis. Acrolein is a potent inhibitor of cell proliferation at nonlethal doses and may act through effects on redox-regulated transcription factors. We previously reported that NF-kappaB activation is inhibited by acrolein in the A549 lung adenocarcinoma cell line in an IkappaB-independent manner [Horton et al. (1999) J. Biol. Chem. 274, 9200-9206]. The current data demonstrate that AP-1 activation in A549 cells is decreased by 26 and 50% at 0.5 and 1 h, respectively, after exposure to 50 fmol/cell (a nonlethal dose) of acrolein. Inhibition of AP-1 activation also occurred following treatment with buthionine sulfoximine to deplete glutathione to the same extent as seen with acrolein. c-jun antisense treatments depressed c-jun protein below detectable levels at 4 h and inhibited cell proliferation (as assessed by [(3)H]thymidine incorporation) by 80%. Immunoprecipitation of c-jun protein after treating A549 cells with acrolein revealed the presence of a lysine-acrolein adduct. There was, however, no effect of acrolein on c-jun N-terminal kinase activity or c-jun phosphorylation. These data indicate that the inhibition of cell proliferation induced by acrolein correlates with the depletion of glutathione as well as the inhibition of AP-1 activation. AP-1 activation is likely affected both through changes in cellular thiol redox balance and by covalent modification of acrolein to c-jun, but not through effects on c-jun phosphorylation.

Acrolein↗
PubMed2005

Mechanism of acrolein-induced vascular toxicity.

Acrolein, an environmental pollutant and a lipid peroxidation product, is implicated in vascular pathogenesis. Although evidence indicates a link between vascular pathogenesis and acrolein, no direct studies relating to effects of acrolein on vascular function and responses are known. This study investigated the effects of acrolein on vascular function to understand the underlying mechanism of acrolein-induced vascular responses. Male Sprague-Dawley rats were treated with acrolein (2 or 4 mg/kg; i.p.) for 3 or 7 days. Urine and blood samples were collected. Changes in systolic blood pressure (SBP) and responses to acetylcholine and phenylephrine were determined. Acrolein (4 mg/kg, 7 days) significantly increased SBP by 25%, phenylephrine vasoconstriction by 2-fold, but decreased urinary excretion of nitrite by 25%. Acrolein inhibited generation of cyclic guanosine 3'5'-monophosphate (cGMP) by 98%, and did not alter expression of nitric oxide synthase (eNOS). Acrolein increased the generation of lipid hydroperoxide in plasma and aortic tissue by 21% and 124% respectively, increased glutathione-S-transferase (GST) and glutathione peroxidase (GSH-Px) activities. Acrolein up-regulated the expression of GST by 2 fold. These data suggest that induced SBP and altered vasoconstriction/vasodilatation in acrolein treated rats may be due to reduced availability of NO via increased free radical generation and reduced antioxidant defense.

Acrolein↗
PubMed2005

Acrolein produces nitric oxide through the elevation of intracellular calcium levels to induce apoptosis in human umbilical vein endothelial cells: implications for smoke angiopathy.

Acrolein is a highly electrophilic alpha, beta-unsaturated aldehyde, the levels of which are increased in the blood of smokers. To determine if acrolein is involved in the pathology of smoke angiopathy, the effect of acrolein on human umbilical vein endothelial cells (HUVEC) was examined. Intracellular nitric oxide (NO) levels, determined using diaminofluorescein-2 diacetate (DAF-2 DA), an NO sensitive fluorescent dye, were found to be increased after treatment in HUVEC with 10 microM acrolein. The measurement of nitrite with 2,3-diaminonaphthalene and a Western blot analysis revealed that nitrite and S-nitroso-cysteine levels were increased in a dose-dependent manner, confirming that NO production is increased by acrolein. The increase was not reduced by treatment with 10mM N-acetyl-l-cysteine (NAC), an anti-oxidant, but was reduced with 10 microM of the intracellular calcium chelator, 1,2-bis (o-aminophenoxy) ethane-N,N,N',N'-tetraacetic acid tetra (acetoxymethyl) ester. Acrolein-stimulated NO production was significantly reduced by pretreatment with 1mM N(G)-nitro-l-arginine-methyl ester (L-NAME), an NO synthase inhibitor. The cytotoxicity of acrolein was reduced by pretreatment with 10 microM 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl 3-oxide (carboxy-PTIO), an intracellular NO scavenger, or 1mM L-NAME, whereas it was not reduced by 10mM NAC, 20 microM Curcumin, another peroxide scavenger, or 100 microM Mn(III)TMPyP, a superoxide dismutase mimic. Nuclear staining and a Western blot analysis using an anti-cleaved caspase 3 antibody revealed that the reduced viability of HUVEC by acrolein was due to apoptosis, which was reversed after pretreatment with 0.1mM carboxy-PTIO or 1mM L-NAME. Thus, acrolein increases intracellular calcium production to induce intracellular NO production by a calcium-dependent NO synthase, possibly eNOS, and the excess and rapid increase in NO might lead to the apoptosis of HUVEC. These data suggest that acrolein might be involved in the pathology of smoke angiopathy through the NO-induced apoptosis of endothelial cells.

Acrolein↗
PubMed1998

Dependence of aldehyde dehydrogenase-mediated oxazaphosphorine resistance on soluble thiols: importance of thiol interactions with the secondary metabolite acrolein.

Acrolein is a highly reactive and cytotoxic by-product released during activation of oxazaphosphorine (OAP) anticancer alkylating agents. Previously, we demonstrated that transfected human aldehyde dehydrogenase (ALDH, EC 1.2.1.3) isozymes (class 1 or 3) protect V79/SD1 cells from mafosfamide (MAF) cytotoxicity, but protection from 4-hydroperoxy-cyclophosphamide (4-hpCPA) was weaker. Acrolein, an ALDH inhibitor, may be detoxified by conjugation with the nucleophilic thiol 2-mercaptoethanesulfonate (MESNA), which is released from MAF but not from 4-hpCPA. We examined the effect of acrolein or acrolein/thiol conjugates on ALDH activity in vitro. We found that both ALDH isozymes were inhibited by acrolein, with IC50 values of 35 and 144 microM for ALDH-1 or ALDH-3, respectively. Both isozymes were partially protected by NAD+ cofactor, being at least five-fold more sensitive to acrolein if added before cofactor. In contrast, thiol conjugates of acrolein did not inhibit ALDH-3 activity, but were substrates only for ALDH-1. Further, acrolein was shown to be oxidized by ALDH-3, but not by ALDH-1. The effect of acrolein on ALDH-mediated resistance to OAP agents in intact cells was also examined. In control cells (without ALDH expression), acrolein and 4-hpCPA rapidly depleted intracellular GSH levels, whereas the effect of MAF was much less. Depletion of GSH by preincubation of V79/SD1 cells with a low concentration of acrolein (2 microM) before MAF exposure caused a two-fold reduction in ALDH-mediated resistance. Conversely, protection from 4-hpCPA cytotoxicity was enhanced by the addition of thiols (GSH, 2-mercaptoethanesulfonate, or N-acetylcysteine) during the drug exposure. These results suggest 1) that thiol content is an important determinant of the OAP resistance conferred by ALDH isoenzymes; and 2) a new mechanism whereby thiol modulation could increase the therapeutic index of OAP chemotherapy.

Acrolein↗