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PubMed1988

Activation of the microsomal glutathione-S-transferase and reduction of the glutathione dependent protection against lipid peroxidation by acrolein.

Allyl alcohol is hepatotoxic. It is generally believed that acrolein, generated out of allyl alcohol by cytosolic alcohol dehydrogenase, is responsible for this toxicity. The effect of acrolein in vitro and in vivo on the glutathione (GSH) dependent protection of liver microsomes against lipid peroxidation, and on the microsomal GSH-S-transferase (GSH-tr) in the rat was determined. In vitro incubation of liver microsomes with 5 mM acrolein for 30 sec resulted in a 2-fold activation of the GSH-tr. This activation probably proceeds via alkylation of the thiol group of the GSH-tr. In vivo administration of 1.1 mmol allyl alcohol/kg to rats did also result in a 2-fold stimulation of the GSH-tr activity. Administration of 375 mg pyrazole/kg, an inhibitor of the alcohol dehydrogenase, thus reducing the acrolein formation, prevented the in vivo stimulation of GSH-tr by allyl alcohol. This indicates that the activation of GSH-tr in vivo by allyl alcohol probably also proceeds via alkylation of the thiol group of the GSH-tr by acrolein. GSH protects liver microsomes against lipid peroxidation, probably via a free radical reductase that reduces vitamin E radicals at the expense of GSH. Incubating liver microsomes for 30 min with 0.1 mM acrolein reduced the GSH dependent protection against lipid peroxidation, probably because an essential thiol group(s) on the free radical reductase is alkylated. In vivo administration of allyl alcohol did not reduce the GSH dependent protection of the microsomes. Probably the thiol group(s) located on the free radical reductase is less accessible or less reactive than the thiol group on the GSH-tr. After administration of allyl alcohol we found no evidence for in vivo lipid peroxidation. Therefore we could not evaluate the importance of the GSH dependent protection against lipid peroxidation in vivo.

1-Propanol↗
PubMed1992

32P-postlabeling of acrolein-deoxyguanosine adducts in DNA after nuclease P1 digestion.

In order to study the relationship between the level of acrolein-DNA adducts and their biological effects, sensitive methods are needed to quantitate DNA adducts. 32P-postlabeling is one such method that has been widely used and we have adapted the technique to detect acrolein-deoxyguanosine adducts. Adducts formed by the reaction of acrolein and deoxyguanosine-3'-monophosphate were isolated by HPLC. Based on their UV spectra and cochromatography with standards after dephosphorylation with acid phosphatase, these adducts were identified as the nucleotide equivalents of cyclic 1,N2-propanodeoxyguanosine adducts formed by acrolein that have been described by Chung et al. [15]. As nucleotides, the adducts were good substrates for polynucleotide kinase-mediated transfer of phosphate from ATP and were able to be detected by 32P-postlabeling. These adducts were resistant to the activity of nuclease P1 and dinucleoside monophosphates in the form d(G*pN) where G* is the acrolein-guanine adduct also resisted digestion by nuclease P1. Digestion of DNA by nuclease P1 and acid phosphatase resulted in the conversion of normal nucleotides to nucleosides and selective enrichment of the adducts as dinucleoside monophosphates. Using nuclease P1/acid phosphatase digestion, followed by 32P-postlabeling and TLC separation, levels of the two adducts in acrolein-treated DNA were found to be about 6185 and 19,222 nmol/mol.

Acid Phosphatase↗
PubMed1983

The effects of acrolein exposure on pulmonary antibacterial defenses.

Inhalation exposure to acrolein induced a dose-dependent impairment of pulmonary antibacterial defenses in mice. Animals exposed to 3 or 6 ppm of acrolein were increasingly less effective in inactivation of aerogenic challenges of 32P-labeled Staphylococcus aureus. Acrolein concentrations greater than 6 ppm caused increased sensory irritations, but no additional impairment of lung antibacterial resistance. Influenza A viral pneumonia in mice also suppressed pulmonary bacterial activity. Mice convalescing from moderate viral pneumonia became severely deficient in antibacterial defenses when exposed to acrolein. Whether the viral-induced impairment in pulmonary defense delayed the inactivation or allowed the proliferation of bacteria was dependent upon the dose of acrolein. The present study demonstrated that an underlying infectious disease process compounded the pulmonary toxicity of acrolein such that normally moderate toxicity was elevated to a virtual abolition of antibacterial defense mechanisms.

Acrolein↗
PubMed1984

Role of acrolein in cyclophosphamide teratogenicity in rat embryos in vitro.

To elucidate the role of acrolein in cyclophosphamide (CP) teratogenesis, we used the dechloro derivative of cyclophosphamide (D-CP). After activation, D-CP spontaneously breaks down to yield acrolein and dechlorophosphoramide mustard (D-PM), the nonalkylating derivative of phosphoramide mustard. At concentrations ranging from 6.25 to 50 micrograms/ml (33 to 262 microM), D-CP produced concentration-dependent cell death, growth retardation, and malformations in rat embryos cultured in vitro from Day 10 to 11 of gestation. D-PM, however, even at a concentration of 238 micrograms/ml (950 microM), had no effect on embryonic growth and development when added directly to standard culture medium containing Day 10 rat embryos. When embryos were exposed to acrolein (0.025 to 0.1 microgram/ml) directly in serum-free medium, this metabolite produced concentration-dependent decreases in growth parameters and abnormal flexion in some embryos. In no case, however, did acrolein-treated embryos resemble D-CP-treated embryos in terms of morphological malformations. Although we were able to show that D-CP was teratogenic in vitro, D-CP doses up to 50 mg/kg administered on Day 11 in vivo had no effect (with the exception of decreased growth at the highest dose) on growth or development at Day 20 of gestation. Our results suggest that acrolein plays a role in CP teratogenesis, but that the form in which it arrives at the teratogenically sensitive sites within the embryo is an important consideration in terms of the relative roles of acrolein and phosphoramide mustard in CP teratogenicity.

Acrolein↗
PubMed1988

Implications for the formation of abasic sites following modification of polydeoxycytidylic acid by acrolein in vitro.

Polydeoxycytidylic acid (poly dC) was incubated with excess acrolein. A Nensorb 20 nucleic acid purification cartridge was used to bind the polymeric material in the poly dC/acrolein reaction mixture. The non-polymeric material eluted from this column had a UV absorbance four times higher than that of the control. The fluorescence spectrum of the eluted material did not correspond to that of unmodified cytosine. Separate aliquots of the reaction mixture were digested to deoxynucleotide 3'-monophosphates by incubation with micrococcal nuclease and spleen phosphodiesterase. The products were converted to 32P-labeled deoxynucleotide 3',5'-bisphosphates by incubation with T4 polynucleotide kinase and excess [gamma-32P]ATP. The 3'-monophosphate was selectively removed by incubation with nuclease P1. Two-dimensional thin-layer chromatography (TLC) on polyethyleneimine cellulose (PEI)-cellulose and detection of 32P-labeled deoxynucleotide 5'-monophosphates by autoradiography failed to provide evidence for the formation of an acrolein adduct of deoxycytidine 5'-monophosphate. When acrolein-modified deoxycytidine 3'-monophosphate was 32P post-labeled, a new product, which co-chromatographed with UV markers synthesized by reaction of acrolein with deoxycytidine 5'-monophosphate, was detected. These data show that acrolein-modified deoxycytidine 3'-monophosphates are substrates for 32P labeling by T4 polynucleotide kinase and are stable under the assay conditions employed. The inability to detect the acrolein-modified nucleotides after reaction with poly dC in vitro suggests that the modified bases are lost from poly dC by cleavage of the N-glycosyl bond resulting in the formation of an abasic site.

Acrolein↗
PubMed2006

Acrolein synthesis from glycerol in hot-compressed water.

Glycerol conversion was conducted in hot-compressed water (HCW: 573-673 K, 25-34.5 MPa) using a batch and a flow apparatus and the influences of temperature, H(2)SO(4), glycerol concentration, and pressure, were examined. The yield of acrolein was enhanced by higher glycerol and H(2)SO(4) concentration, and higher pressure. Approximately 80% selectivity of acrolein was obtained at 90% of glycerol conversion with an acid catalyst in supercritical condition (673 K and 34.5 MPa). The rate constant of acrolein decomposition was always higher than that of acrolein formation in the absence of acid catalyst but the rate constant of acrolein formation could be overcome that of acrolein decomposition by addition acid in supercritical condition.

Acrolein↗
PubMed2004

Levels and determinants of formaldehyde, acetaldehyde, and acrolein in residential indoor air in Prince Edward Island, Canada.

This study was undertaken to determine the concentrations of formaldehyde, acetaldehyde, and acrolein in air samples taken in some Canadian houses and to determine the association between aldehyde levels and housing characteristics. Concentrations of formaldehyde, acetaldehyde, and acrolein were measured in 59 homes in Prince Edward Island, Canada, during the winter of 2002. Housing characteristics were documented through inspection and by interviews of occupants. Formaldehyde, acetaldehyde, and acrolein concentrations ranged from 5.5 to 87.5 microg/m(3) (median, 29.6 microg/m(3)), from 4.4 to 79.1 microg/m(3) (median, 18.9 microg/m(3)), and from 0.1 to 4.9 microg/m(3) (median, 0.9 microg/m(3)), respectively. Formaldehyde levels were elevated in homes built after 1970. Acetaldehyde and acrolein levels were elevated in homes inhabited by at least one smoker and in homes built 1970--1985 and were correlated with absolute humidity and carbon dioxide, two variables likely to be surrogates for lower air exchange rates. In conclusion, lower air exchange rates appear to be important determinants of formaldehyde, acetaldehyde, and acrolein levels in homes. These data also confirm that smoking is a significant source of acetaldehyde and acrolein and indoor air.

Acetaldehyde↗
PubMed2004

Monitoring of urinary acrolein concentration in patients receiving cyclophosphamide and ifosphamide.

Acrolein, the metabolite of cyclophosphamide and ifosphamide, irritates mucous membranes and is considered pathogenetically important in hemorrhagic cystitis. Increasing fluid intake or administering sodium 2-mercaptoethanesulfonate (mesna), a thiol compound, can reduce the risk of this complication. We measured urinary acrolein concentrations using headspace-solid-phase microextraction gas chromatography and mass spectrometry (headspace-SPME-GC-MS) in 19 patients receiving cyclophosphamide and ifosphamide (36 occasions). Peak acrolein concentrations occurred at 1-12h (mean +/- S.D., 5.0+/-2.7) after starting therapy, ranging from 0.3 to 406.8 nM (39.7+/-76.7), with varying patterns over time. Maintaining high urine volume was important for preventing increases in urinary acrolein concentration, as urinary acrolein concentration tended to rise as urine volume decreased. Urinalysis detected occult blood in three cases, but the patients had no clinical symptoms of hemorrhagic cystitis. In clinical trials involving cyclophosphamide and ifosphamide, monitoring of urinary acrolein concentration could indicate when to take heightened preventive measures against hemorrhagic cystitis.

Acrolein↗
PubMed2004

Acrolein induces oxidative stress in brain mitochondria.

Acrolein, a byproduct of lipid peroxidation, has been shown to inflict significant structural and functional damage to isolated guinea pig spinal cord. Reactive oxygen species (ROS) are thought to mediate such detrimental effects. The current study demonstrates that acrolein can directly stimulate mitochondrial oxidative stress. Specifically, exposure of purified brain mitochondria to acrolein resulted in a dose-dependent increase of ROS and decreases in glutathione content and aconitase activity. This effect was not accompanied by significant intramitochondrial calcium influx or mitochondrial permeability transition, but rather by impaired function of the mitochondrial electron transport system. As well, we detected a significant inhibition of mitochondrial adenine nucleotide translocase (ANT) in the presence of acrolein. This inhibition of ANT likely contributes to acrolein-induced ROS elevation since application of atractyloside, a specific ANT inhibitor, induced significant increase of ROS. We hypothesize that inhibition of ANT may mediate, in part, the acrolein-induced ROS increase in mitochondria.

Acrolein↗
PubMed2006

Measurement of acrolein and 1,3-butadiene in a single puff of cigarette smoke using lead-salt tunable diode laser infrared spectroscopy.

Acrolein and 1,3-butadiene in cigarette smoke generally are measured using two separate analytical methods, a carbonyl derivative HPLC method for acrolein and a volatile organic compound (VOC) GC/MS method for 1,3-butadiene. However, a single analytical method having improved sensitivity and real-time per puff measurement will offer more specific information for evaluating experimental carbon filtered cigarettes designed to reduce the smoke deliveries of these constituents. This paper describes an infrared technique using two lead-salt tunable diode lasers (TDLs) operating with liquid nitrogen cooling with emissions at 958.8 cm(-1) and 891.0 cm(-1) respectively for the simultaneous measurement of acrolein and 1,3-butadiene, respectively, in each puff of mainstream cigarette smoke in real time. The dual TDL system uses a 3.1l volume, 100 m astigmatic multiple pass absorption gas cell. Quantitation is based on a spectral fit that uses previously determined infrared molecular line parameters generated in our laboratory, including line positions, line strengths and nitrogen-broadened half-widths for these species. Since acrolein and ethylene absorption lines overlap and 1,3-butadiene, ethylene and propylene absorption lines overlap, the per puff deliveries of ethylene and propylene were determined since their overlapping absorption lines must be taken into account by the spectral fit. The acrolein and 1,3-butadiene total cigarette deliveries for the 1R5F Kentucky Reference cigarette were in agreement with the HPLC and GC/MS methods, respectively. The limit of detection (LOD) for 1,3-butadiene and acrolein was 4 ng/puff and 24 ng/puff, respectively, which is more than adequate to determine at which puff they break through the carbon filter. The retention and breakthrough behavior for the two primary smoke constituents depend on the cigarette design and characteristics of the carbon filter being evaluated.

Acrolein↗
PubMed2003

Ischemic insult exacerbates acrolein-induced conduction loss and axonal membrane disruption in guinea pig spinal cord white matter.

Cellular destruction following ischemic insult may be due to secondary injury mechanisms, not the oxygen-glucose deprivation itself. We have examined the effect of acrolein, an aldehyde product of lipid peroxidation (LPO) and oxidative stress, on the axons in isolated guinea pig spinal cord white matter following ischemic insult. We have found that acrolein at 50 microM, which is unharmful to spinal cord when applied alone, causes action potential conduction failure and membrane disruption following 1 to 2 h of exposure when applied during the reperfusion period. Ischemic insult also exacerbates the effect of acrolein at 200 microM, which does inflict functional and anatomical damage when applied alone. Unlike metabolic poisoning, acrolein-mediated damage is not a function of axonal size and does not affect the refractoriness in response to dual and multiple stimuli. These results indicate that spinal cord axons, in addition to experiencing elevated free radicals, are more vulnerable to acrolein attack when the level of oxygen and glucose is low. We conclude that free radicals and lipid peroxidation in general, and acrolein in specific, may play a critical role in cellular destruction and functional loss in such injury.

Acrolein↗
PubMed2000

Acrolein, a product of lipid peroxidation, inhibits glucose and glutamate uptake in primary neuronal cultures.

Oxidative stress has been implicated in the pathogenesis of several neurodegenerative disorders 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 patients with AD. Acrolein, an alpha,beta-unsaturated aldehydic product of lipid peroxidation has been demonstrated to be approximately 100 times more reactive than HNE and is present in neurofibrillary tangles in the brain in AD. We recently demonstrated statistically significant elevated concentrations of extractable acrolein in the hippocampus/parahippocampal gyrus and amygdala in AD compared with age-matched control subjects. Concentrations of acrolein were two to five times those of HNE in the same samples. Treatment of hippocampal cultures with acrolein led to a time- and concentration-dependent decrease in cell survival as well as a concentration-dependent increase in intracellular calcium. In cortical neuron cultures, we now report that acrolein causes a concentration-dependent impairment of glutamate uptake and glucose transport in cortical neuron cultures. Treatment of cortical astrocyte cultures with acrolein led to the same pattern of impairment of glutamate uptake as observed in cortical neuron cultures. Collectively, these data demonstrate neurotoxicity mechanisms of arolein that might be important in the pathogenesis of neuron degeneration in AD.

Acrolein↗
PubMed2003

Inactivation of acrolein by sodium 2-mercaptoethanesulfonate using headspace-solid-phase microextraction gas chromatography and mass spectrometry.

Acrolein, the metabolite of cyclophosphamide and ifosphamide, is an irritant of mucous membranes and seems to play an important role in hemorrhagic cystitis. Several methods are available to reduce the risk of hemorrhagic cystitis. Mesna is a regional detoxificant which inactivates acrolein. However, the interaction of mesna and acrolein has never been reported because no available method can detect acrolein. In this study, we measured acrolein to evaluate the effect of mesna in urine or phosphate-buffered saline using a headspace-solid-phase microextraction gas chromatography and mass spectrometry method which we had previously established. We also investigated the effect of mesna at different conditions of pH. Mesna was effective in a dose-dependent (10 microM to 20 mM) fashion in both urine and phosphate-buffered saline and completely inactivated acrolein at concentrations over 10 mM. Furthermore, mesna was more effective in alkaline conditions than in acid.

Acrolein↗
PubMed2002

Ambient air measurement of acrolein and other carbonyls at the Oakland-San Francisco Bay Bridge toll plaza.

Interest in ambient concentrations of acrolein and other alpha,beta-unsaturated aldehydes and dicarbonyls (e.g., crotonaldehyde, methyl glyoxal, glyoxal, malonaldehyde (malondialdehyde)) is growing because either they exist at high levels in motor vehicle emissions or they arise from photooxidation of other hydrocarbons emitted from mobile sources. In addition, their mutagenic, genotoxic, or carcinogenic properties are well-established, and the results of a dispersion-modeling study regarding the health risks posed by the 188 hazardous air pollutants in California attributes the highest noncancer risk to exposure to acrolein. Such modeling studies, conducted by the U.S. Environmental Protection Agency (U.S. EPA), also predict median ambient air concentrations of acrolein higher than 0.06 microg/m3, the chronic inhalation reference exposure level stipulated by the California Office of Environmental Health Hazard Assessment in counties surrounding the Oakland-San Francisco Bay Bridge. We measured acrolein and other potentially toxic carbonyls in air sampled at the San Francisco Bay Bridge toll plaza during rush hour traffic, which may be considered a "worst case scenario" for outdoor airborne carbonyls. We identified 36 carbonyls in the sample extracts, including 14 saturated aliphatic carbonyls, six unsaturated carbonyls, four aromatic carbonyls, six dicarbonyls, and six hydroxy carbonyls. Structural information to support tentative identification of carbonyls and hydroxycarbonyls was obtained by using a method that involves O-(2,3,4,5,6-pentafluorobenzyl)hydroxylamine (PFBHA) and PFBHA/bis(trimethylsilyl)trifluoroacetamide (BSTFA) derivatization in concert with gas chromatography/ion trap mass spectrometry. Most notably, we report for the first time the presence of malonaldehyde in the ambient atmospheric environment. A relatively linear relationship between retention time and the molecular weight of the derivatives was established to assist in obtaining structural information about chemicals for which authentic standards are not readily available. Levels of acrolein exceeded the California reference exposure level during morning rush hour traffic. The measured values, however, were significantly lower than estimates of county-wide average acrolein concentrations predicted by a U.S. EPA modeling study based on 1996 data. Successful regulatory efforts such as the introduction of reformulated gasoline, together with the advancement of new catalysts and fleet turnover throughout the 1990s, are likely to account for part of the gap between our determination and the 1996 levels.

Acrolein↗
PubMedDate not supplied

Bioactivation mechanism of S-(3-oxopropyl)-N-acetyl-L-cysteine, the mercapturic acid of acrolein.

S-(3-Oxopropyl)glutathione, the glutathione conjugate of acrolein, has been reported to be nephrotoxic. The objective of the present studies was to investigate the bioactivation mechanism of the analogues S-(3-oxopropyl)-N-acetyl-L-cysteine (1) and S-(3-oxopropyl)-N-acetyl-L-cysteine S-oxide (2) and to test the hypothesis that the cytotoxicity of 1 is associated with its latent potential to release acrolein in kidney cells. Mechanistic considerations indicated that sulfoxidation of sulfide 1 to form S-oxide 2 and a subsequent general-base-catalyzed beta-elimination reaction would release the cytotoxin acrolein. Hence the release of acrolein from 1 and 2 was studied in chemical systems, and their cytotoxicity was investigated in cultured LLC-PK1 cells and in isolated rat renal proximal tubular cells. Acrolein formation from S-oxide 2, but not from sulfide 1, was observed under basic conditions and with phosphate as the base. Kinetic analysis indicated that a general-base-catalyzed reaction was involved. Both S-conjugates 1 and 2 were cytotoxic in LLC-PK1 cells and in isolated rat renal proximal tubular cells, and the cytotoxicity of sulfide 1, but not of S-oxide 2, in isolated renal proximal tubular cells was reduced in presence of methimazole, an inhibitor of the flavin-containing monooxygenase. These findings indicate that the cytotoxicity of S-conjugate 1 is associated with a novel bioactivation mechanism that involves sulfoxidation followed by a general-base-catalyzed elimination of acrolein from S-oxide 2.

Acetylcysteine↗
PubMedDate not supplied

Characterization of 2'-deoxycytidine and 2'-deoxyuridine adducts formed in reactions with acrolein and 2-bromoacrolein.

The products of the reaction of the mutagenic aldehydes, acrolein and 2-bromoacrolein, with 2'-deoxycytidine and 2'-deoxyuridine have been determined. These products, formed at physiological conditions, were isolated by reverse-phase HPLC and characterized by UV, 1H NMR, fast atom bombardment MS, electrospray MS, and chemical transformation. The reaction of 2'-deoxycytidine with acrolein and 2-bromoacrolein produced the exocyclic compounds 3-(2'-deoxyribosyl)-7,8,9-trihydro-7-hydroxypyrimido[3,4- c]pyrimidin-2-one and 3-(2'-deoxyribosyl)-7,8,9-trihydro-7-hydroxy-8-bromopyrimido [3,4-c] pyrimidin-2-one, respectively. In addition to the chiral centers of deoxyribose, one new chiral center was formed from C-1 of acrolein and two new chiral centers were formed from C-1 and C-2 of 2-bromoacrolein, creating a mixture of diastereomers for each product. These compounds are not stable in basic solution and undergo ring opening and hydrolytic deamination, resulting in 2'-deoxyuridine adducts. The N3-alkylated 2'-deoxyuridines were also synthesized by permitting 2'-deoxyuridine to react with 2-bromoacrolein and acrolein. An unstable intermediate, N3-(2"-bromo-3"-oxopropyl)-2'-deoxyuridine, was also isolated and characterized from the reaction with 2-bromoacrolein. The reaction of 2'-deoxyuridine with acrolein gave N3-(3"-oxopropyl)-2'-deoxyuridine as the major product, which was reduced to its corresponding alcohol with NaBH4. Reactions of 2'-deoxycytidine with 2-bromoacrolein and acrolein proceed most rapidly at acidic or neutral pH; however, 2'-deoxyuridine reacts most rapidly at neutral or basic pH.

Acrolein↗
PubMed2006

Tissue distribution of lipid peroxidation product acrolein in human colon carcinogenesis.

Lipid peroxidation product acrolein, well-known pollutant in tobacco and automotive smoke, accumulates in vivo bound to proteins. It suppresses p53 synthesis acting as potent carcinogenic factor for oral, respiratory and bladder carcinomas, while its possible association with colon carcinogenesis was not studied so far. We used genuine monoclonal antibody to evaluate immunohistochemical distribution of acrolein-protein adducts in 113 human colon tumours. The presence of acrolein-protein adducts was increasing with respect to colon carcinogenesis, from moderate appearance in tubular and villotubular low-grade adenomas to abundant and diffuse distribution in high-grade villotubular adenomas and Dukes A carcinomas. However, in advanced Dukes B and C carcinomas acrolein was hardly noticed, although, its protein adducts were found abundant in non-malignant colon epithelium of these patients. There was no relationship between p53 and acrolein distribution. According to these findings, acrolein seems to be lipid peroxidation product associated with transition from benign into malignant colon tumours.

Acrolein↗
PubMed1993

Thiol status and cytopathological effects of acrolein in normal and xeroderma pigmentosum skin fibroblasts.

Thiol redox status was determined in normal human skin fibroblasts and a DNA repair-deficient xeroderma pigmentosum (XP) fibroblast cell line (XP12BE, group A), and cytotoxic and genotoxic effects of the thiol-reactive aldehyde acrolein were studied in these cell types. Normal cells contained higher amounts of the reduced glutathione and cysteine respectively, and higher amounts of these thiols as protein-bound disulfides than the XP cells. However, in both cell types total glutathione was present in 6- to 7-fold higher amounts than total cysteine, and total protein thiols corresponded to approximately 30% of total thiols. A 1 h exposure to acrolein caused a quantitatively similar depletion of reduced glutathione and free protein thiols in both cell types, without causing changes in the thiol redox state. However, acrolein caused higher toxicity measured as trypan blue exclusion, and also a higher extent of DNA single-strand breaks in the XP cells than in the normal cells. Exposure to acrolein, followed by incubation in fresh medium resulted in continued formation of DNA single-strand breaks in the normal cells, whereas no such accumulation occurred in the XP cells. In the normal cells, the DNA single-strand breaks accumulated to a similar extent as in the presence of 1-beta-D-arabinofuranosyl-cytosine and hydroxyurea, i.e. two agents which together efficiently inhibit DNA repair synthesis. The results indicate quantitative and qualitative differences in the thiol redox state between normal and XP cells, and that these differences may contribute to the higher cytotoxicity and genotoxicity of acrolein in XP cells. Moreover, the results indicate that acrolein is a potent inhibitor of DNA excision repair.

Acrolein↗