4-hydroxy-2-nonenal and 2-butenal

The process of lipid oxidation generates a diverse array of small aldehydes and carbonyl-containing compounds, which may occur in free form or esterified within phospholipids and cholesterol esters. These aldehydes mostly result from fragmentation of fatty acyl chains following radical oxidation, and the products can be subdivided into alkanals, alkenals (usually α,β-unsaturated), γ-substituted alkenals and bis-aldehydes. Isolevuglandins are non-fragmented di-carbonyl compounds derived from H

Topics: Acrolein; Aldehydes; Animals; Humans; Isoprostanes; Lactoglobulins; Lipid Peroxidation; Oxidative Stress; Protein Processing, Post-Translational

The alpha,beta-unsaturated aldehydes (enals) acrolein, crotonaldehyde, and trans-4-hydroxynonenal (4-HNE) are products of endogenous lipid peroxidation, arising as a consequence of oxidative stress. The addition of enals to dG involves Michael addition of the N(2)-amine to give N(2)-(3-oxopropyl)-dG adducts, followed by reversible cyclization of N1 with the aldehyde, yielding 1,N(2)-dG exocyclic products. The 1,N(2)-dG exocyclic adducts from acrolein, crotonaldehyde, and 4-HNE exist in human and rodent DNA. The enal-induced 1,N(2)-dG lesions are repaired by the nucleotide excision repair pathway in both Escherichia coli and mammalian cells. Oligodeoxynucleotides containing structurally defined 1,N(2)-dG adducts of acrolein, crotonaldehyde, and 4-HNE were synthesized via a postsynthetic modification strategy. Site-specific mutagenesis of enal adducts has been carried out in E. coli and various mammalian cells. In all cases, the predominant mutations observed are G-->T transversions, but these adducts are not strongly miscoding. When placed into duplex DNA opposite dC, the 1,N(2)-dG exocyclic lesions undergo ring opening to the corresponding N(2)-(3-oxopropyl)-dG derivatives. Significantly, this places a reactive aldehyde in the minor groove of DNA, and the adducted base possesses a modestly perturbed Watson-Crick face. Replication bypass studies in vitro indicate that DNA synthesis past the ring-opened lesions can be catalyzed by pol eta, pol iota, and pol kappa. It also can be accomplished by a combination of Rev1 and pol zeta acting sequentially. However, efficient nucleotide insertion opposite the 1,N(2)-dG ring-closed adducts can be carried out only by pol iota and Rev1, two DNA polymerases that do not rely on the Watson-Crick pairing to recognize the template base. The N(2)-(3-oxopropyl)-dG adducts can undergo further chemistry, forming interstrand DNA cross-links in the 5'-CpG-3' sequence, intrastrand DNA cross-links, or DNA-protein conjugates. NMR and mass spectrometric analyses indicate that the DNA interstand cross-links contain a mixture of carbinolamine and Schiff base, with the carbinolamine forms of the linkages predominating in duplex DNA. The reduced derivatives of the enal-mediated N(2)-dG:N(2)-dG interstrand cross-links can be processed in mammalian cells by a mechanism not requiring homologous recombination. Mutations are rarely generated during processing of these cross-links. In contrast, the reduced acrolein-mediated N(2)-dG peptide co

Topics: Acrolein; Aldehydes; Base Sequence; Deoxyguanosine; DNA Adducts; DNA Repair; Mutagenesis; Oligodeoxyribonucleotides

Topics: Acrolein; Aging; Aldehydes; Animals; Carcinogens; Cross-Linking Reagents; DNA Adducts; Humans; Liver; Malondialdehyde; Mice; Mutation; Oxidation-Reduction; Rats; Structure-Activity Relationship

Topics: Acrolein; Aldehydes; Animals; Base Sequence; DNA; DNA Adducts; Malondialdehyde; Molecular Sequence Data; Pyruvaldehyde; Structure-Activity Relationship

The purpose of this study was to assess the processes of lipid peroxidation with prostaglandin derivatives and reactive aldehydes being its major indicators in cerebrospinal fluid (CSF), plasma and urine of patients with tick-borne encephalitis (TBE).. This study included 60 patients with TBE and 56 healthy subjects. Lipid peroxidation was estimated by the measurement of 4-hydroxynonenal (4-HNE), 4-hydroxyhexenal (4-HHE), malondialdehyde (MDA), acrolein, crotonaldehyde, and 4-oxononenal (4-ONE), determined by GC-MS, F2-isoprostanes and neuroprostanes (NPs) level determined by LC-MS. The level of 4-HNE-protein adducts was determined by ELISA. Phospholipase A2 (PLA2), platelet-activating factor acetylhydrolase (PAF-AH) and glutathione peroxidase (GSH-Px) activities and vitamin E level were determined spectrophotometrically and by HPLC, respectively. In parallel, the plasma levels of phospholipid acids such as arachidonic acid (AA), linoleic acid (LA) and docosahexaenoic acid (DHA) were monitored.. A significant decrease in AA, LA, DHA level and GSH-Px activity (by about 20, 69, 11 and 18%, respectively) was observed. The consequence of enhanced phospholipid peroxidation was almost 7 times higher plasma level of F2-isoprostanes and 3-fold increase in NPs level in CSF of TBE patients. Additionally a 3.5-fold increase in the CSF level of MDA, 5-fold increase in the plasma level of 4-HNE and urine level of 4-HHE in TBE patients was observed. Decreased plasma activity of PLA2 with an increase in the PAF-AH activity was observed.. Lipid peroxidation occurring during TBE development indicates its relevance in pathophysiology of this disease. Moreover lipid peroxidation products might be useful for the diagnosis of TBE.

Topics: Adult; Aged; Aged, 80 and over; Aldehydes; Biomarkers; Case-Control Studies; Encephalitis, Tick-Borne; Fatty Acids; Female; Humans; Lipid Peroxidation; Male; Malondialdehyde; Middle Aged; Phospholipids; Young Adult

Aldo-keto reductase (AKR) enzymes are critical for the detoxication of endogenous and exogenous aldehydes. Previous studies have shown that the AKR7A2 enzyme is catalytically active toward aldehydes arising from lipid peroxidation, suggesting a potential role against the consequences of oxidative stress, and representing an important detoxication route in mammalian cells. The aim of this study was to determine the ability of AKR7A2 to protect cells against aldehyde cytotoxicity and genotoxicity and elucidate its potential role in providing resistance to oxidative stress. A transgenic mammalian cell model was developed in which AKR7A2 was overexpressed in V79-4 cells and used to evaluate the ability of AKR7A2 to provide resistance against toxic aldehydes. Results show that AKR7A2 provides increased resistance to the cytotoxicity of 4-hydroxynonenal (HNE) and modest resistance to the cytotoxicity of trans, trans-muconaldehyde (MUC) and methyglyoxal, but provided no protection against crotonaldehyde and acrolein. Cells expressing AKR7A2 were also found to be less susceptible to DNA damage, showing a decrease in mutation rate cause by 4-HNE compared to control cells. Furthermore, the role of the AKR7A2 enzyme on the cellular capability to cope with oxidative stress was assessed. V79 cells expressing AKR7A2 were more resistant to the redox-cycler menadione and were able to lower menadione-induced ROS levels in both a time and dose dependent manner. In addition, AKR7A2 was able to maintain intracellular GSH levels in the presence of menadione. Together these findings indicate that AKR7A2 is involved in cellular detoxication pathways and may play a defensive role against oxidative stress in vivo.

Topics: Acrolein; Aldehyde Reductase; Aldehydes; Animals; Caspase 3; Cell Line; Cricetinae; DNA Damage; Glutathione; Humans; Mutagenicity Tests; Oxidative Stress; Pyruvaldehyde; Reactive Oxygen Species

The transient receptor potential subfamily A member 1 (TRPA1) is a non-selective cation channel implicated in the pathogenesis of several airway diseases like asthma and chronic obstructive pulmonary disease (COPD). Most of the research on TRPA1 focuses on its expression and function in neuronal context; studies investigating non-neuronal expression of TRPA1 are lacking. In the present study, we show functional expression of TRPA1 in human lung fibroblast cells (CCD19-Lu) and human pulmonary alveolar epithelial cell line (A549). We demonstrate TRPA1 expression at both mRNA and protein levels in these cell types. TRPA1 selective agonists like allyl isothiocyanate (AITC), 4-hydroxynonenal (4-HNE), crotonaldehyde and zinc, induced a concentration-dependent increase in Ca+2 influx in CCD19-Lu and A549 cells. AITC-induced Ca+2 influx was inhibited by Ruthenium red (RR), a TRP channel pore blocker, and by GRC 17536, a TRPA1 specific antagonist. Furthermore, we also provide evidence that activation of the TRPA1 receptor by TRPA1 selective agonists promotes release of the chemokine IL-8 in CCD19-Lu and A549 cells. The IL-8 release in response to TRPA1 agonists was attenuated by TRPA1 selective antagonists. In conclusion, we demonstrate here for the first time that TRPA1 is functionally expressed in cultured human lung fibroblast cells (CCD19-Lu) and human alveolar epithelial cell line (A549) and may have a potential role in modulating release of this important chemokine in inflamed airways.

Topics: Aldehydes; Calcium; Calcium Channels; Cations, Divalent; Cells, Cultured; Chlorides; Dose-Response Relationship, Drug; Epithelial Cells; Fibroblasts; Humans; Interleukin-8; Isothiocyanates; Nerve Tissue Proteins; Ruthenium Red; Transient Receptor Potential Channels; TRPA1 Cation Channel; Zinc Compounds

Several studies have documented the involvement of oxidative stress represented by lipid peroxidation in the pathogenesis of Alzheimer's disease (AD). To test whether the highly reactive carbonyl crotonaldehyde (CRA), generated during lipid peroxidation, is involved in AD, we performed an immunohistochemical analysis in AD and age-matched control hippocampi using a specific antibody against protein-bound CRA (P-CRA). In the AD cases, P-CRA immunoreactivity was preferentially localized in reactive astrocytes and microglia around senile plaques (SPs) and those present in the neuropil, while it was weakly detectable in neurons and neurofibrillary tangles. P-CRA immunoreactivity was also localized in all portions of diffuse SPs and the dystrophic neurites of neuritic and classical SPs, but was undetectable in amyloid cores. Age-matched controls showed P-CRA immunoreactivity only very weakly in neurons. In contrast to P-CRA, immunoreactivities for protein-bound acrolein and 4-hydroxy-2-nonenal were mainly localized to neurons and rarely seen in glial cells. Our results suggest that increased oxidative stress and CRA formation in glial cells is implicated in the disease processes of AD.

Topics: Acrolein; Aged; Aged, 80 and over; Aldehydes; Alzheimer Disease; Astrocytes; Brain; Female; Humans; Lipid Peroxidation; Male; Middle Aged; Neuroglia; Oxidative Stress

DNA-protein cross-links (DPCs) are formed upon exposure to a variety of chemical and physical agents and pose a threat to genomic integrity. In particular, acrolein and related aldehydes produce DPCs, although the chemical linkages for such cross-links have not been identified. Here, we report that oligodeoxynucleotides containing 1,N(2)-deoxyguanosine adducts of acrolein, crotonaldehyde, and trans-4-hydroxynonenal can form cross-links with the tetrapeptide Lys-Trp-Lys-Lys. We concluded that complex formation is mediated by a Schiff base linkage because DNA-peptide complexes were covalently trapped following reduction with sodium cyanoborohydride, and pre-reduction of adducted DNAs inhibited complex formation. A previous NMR study demonstrated that duplex DNA catalyzes ring opening for the acrolein-derived gamma-hydroxy-1,N(2)-propanodeoxyguanosine adduct to yield an aldehydic function (de los Santos, C., Zaliznyak, T., and Johnson, F. (2001) J. Biol. Chem. 276, 9077-9082). Consistent with this earlier observation, the adducts under investigation were more reactive in duplex DNA than in single-stranded DNA, and we concluded that the ring-open aldehydic moiety is the induced tautomer in duplex DNA for adducts exhibiting high relative reactivity. Adducted DNA cross-linked to Arg-Trp-Arg-Arg and Lys-Trp-Lys-Lys with comparable efficiency, and N(alpha)-acetylation of peptides dramatically inhibited trapping; thus, the reactive nucleophile is located at the N-terminal alpha-amine of the peptide. These data suggest that Schiff base chemistry can mediate DPC formation in vivo following the formation of stable aldehyde-derived DNA adducts.

Topics: Acrolein; Aldehydes; Amino Acid Sequence; Cross-Linking Reagents; Deoxyguanosine; DNA Adducts; Kinetics; Models, Molecular; Molecular Structure; Oligopeptides; Schiff Bases

The tumorigenicity of chloral hydrate (CH), trichloroacetic acid (TCA), trichloroethanol (TCE), malondialdehyde (MDA), crotonaldehyde, acrolein, and 4-hydroxy-2-nonenal (HNE) was tested in the B6C3F(1) neonatal mouse. Mice were administered i.p. injections of CH (1000, 2000, 2500, and 5000 nmol per animal), TCA (1000 and 2000 nmol), TCE (1000 and 2000 nmol), MDA (1500 and 3000 nmol), crotonaldehyde (1500 and 3000 nmol), acrolein (75 and 150 nmol), and HNE (750 and 1500 nmol) at 8 and 15 days of age. At 12 months, only male mice treated with the positive control chemicals, 4-aminobiphenyl (500 and 1000 nmol) and benzo[a]pyrene (150 and 300 nmol), had incidences of tumors in the liver significantly higher than the solvent control. Additional male mice were dosed as described above and their livers were excised at 24, 48 h, and 7 days after the final dose. Liver DNA was isolated and analyzed by 32P-postlabeling/high-performance liquid chromatography (HPLC) and HPLC/electrochemical detection for MDA-derived adduct (M(1)G) and 8-oxo-2'-deoxyguanosine (8-OHdG) formation, respectively. At 24 and 48 h after the final dose, CH- and TCA-treated mice exhibited significantly higher M(1)G levels than the controls. 8-OHdG formation was also induced by CH, TCA, and MDA. These results suggest that under these experimental conditions the B6C3F(1) neonatal mouse is not sensitive to carcinogens that induce an increase in endogenous DNA adduct formation through lipid peroxidation or oxidative stress.

Topics: Acrolein; Aldehydes; Animals; Animals, Newborn; Carcinogenicity Tests; Carcinogens; Chloral Hydrate; Chromatography, High Pressure Liquid; Crosses, Genetic; DNA; DNA Adducts; Electrochemistry; Ethylene Chlorohydrin; Female; Lipid Peroxidation; Liver; Liver Neoplasms, Experimental; Male; Malondialdehyde; Mice; Mice, Inbred C3H; Mice, Inbred C57BL; Microsomes, Liver; Phosphorus Radioisotopes; Trichloroacetic Acid

Lipid peroxidation due to oxidative stress is accelerated under hyperglycemic conditions such as diabetes mellitus. The effect of 4-hydroxy-2-nonenal (HNE) and other lipid peroxidation products on the ability of isolated rat pancreatic islets to secrete insulin was examined in this study. HNE concentration- and time-dependently deteriorated glucose-induced insulin secretion: insulin secretion was decreased by 50% when measured after incubation of islets with 100 microM HNE for 1 h. Other lipid peroxidation products, e.g. 2-hexenal and 2-butenal, also inhibited glucose-induced insulin secretion. HNE at 100 microM lowered alpha-ketoisocaproate-induced insulin secretion, whereas leucine-induced insulin secretion was stimulated. Insulin secretion induced by 10 mM glyceraldehyde was slightly decreased by HNE. On the other hand, HNE severely decreased insulin secretion induced by 10 mM glyceraldehyde and 2.8 mM glucose. Glucose utilization and glucose oxidation were significantly lowered in islets treated with HNE. The amounts of fructose 1,6-bisphosphate and dihydroxyacetone phosphate in islets were decreased by treatment with HNE, whereas the amount of fructose 6-phosphate was increased. Our study indicates that HNE and other lipid peroxidation products impair insulin secretion induced by glucose probably through affecting both the glycolytic pathway and the citric acid cycle.

Topics: Aldehydes; Animals; Citric Acid Cycle; Dihydroxyacetone Phosphate; Female; Fructosediphosphates; Glucose; Glyceraldehyde; Glycolysis; Insulin; Insulin Secretion; Islets of Langerhans; Keto Acids; Leucine; Lipid Peroxidation; Oxidative Stress; Rats; Rats, Wistar

Aldose reductase (AR) is a member of the aldo-keto reductase superfamily. Due to its ability to catalyze the formation of sorbitol from glucose during hyperglycemic and hypertonic stress, the aldose-reducing property of AR has been accepted as its main physiological and pathological function. Nonetheless, AR is a poor catalyst for glucose reduction and displays active-site properties unexpected of a carbohydrate-binding protein. We, therefore, examined the catalytic properties of AR with a series of naturally occurring aldehydes, compatible in their hydrophobicity to the large apolar active site of the enzyme. Our results show that recombinant human AR is an efficient catalyst for the reduction of medium- to long-chain unbranched saturated and unsaturated aldehydes. The enzyme displayed selective preference for saturated aldehydes, such as hexanal, and unsaturated aldehydes, such as trans-2-octenal and nonenal as well as their 4-hydroxy derivatives. Short-chain aldehydes such as propanal and acrolein were reduced less efficiently. Branched derivatives of acrolein or its glutathione conjugate (GS-propanal) were, however, reduced with high efficiency. In the absence of NADPH, the alpha, beta unsaturated aldehydes caused covalent modification of the enzyme. On the basis of electrospray mass spectrometric analysis of the wild-type and site-directed mutants of AR (in which the solvent exposed cysteines were individually replaced with serine), the site of modification was identified to be the active-site residue, Cys 298. The unsaturated aldehydes, however, did not modify the enzyme bound to NADPH and did not inactivate the enzyme during catalysis. Modeling studies indicate that the large hydrophobic active site of AR can accommodate a large number of aldehydes without changes in the structure of the binding site or movement of side chains. High hydrophobicity due to long alkyl chains or apolar substituents appears to stabilize the interaction of the aldehyde substrates with the enzyme. Apparently, such hydrophobic interactions provide substrate selectivity and catalytic efficiency of the order achievable by hydrogen bonding. Since several of the aldehydes reduced by AR are either environmental and pharmacological pollutants or products of lipid peroxidation, the present studies provide the basis of future investigations on the role of AR in regulating aldehyde metabolism particularly under pathological states associated with oxidative stress and/or aldehyde to

Topics: Aldehyde Reductase; Aldehydes; Catalysis; Computer Simulation; Humans; Kinetics; Mass Spectrometry; Models, Molecular; Oxidation-Reduction; Substrate Specificity

An important emerging issue in chemical carcinogenesis is the role that products of endogenous metabolism play in formation of covalently modified DNA. One example is the formation of alpha, beta-unsaturated aldehydes as a result of endogenous and drug-stimulated lipid peroxidation. Malondialdehyde (MDA), crotonaldehyde (CR), 2-hexenal (HX), and 4-hydroxy-2-nonenal (HNE) react covalently with 2'-deoxyguanosine (dG) and 2'-deoxyadenosine (dA) residues on DNA to form promutagenic cyclic adducts that may be important in the etiology of cancer in humans and animals. The accurate quantification of such adducts provides a powerful tool in molecular epidemiology for assessing carcinogenic risks from various lifestyle choices (e.g. diet, drug use) in humans. 32P-Postlabeling is recognized as one of the most sensitive methods available for detection of DNA adducts in human tissues, but without adequate validation such methodology can yield inaccurate quantitative measurements. We have used LC separations in conjunction with electrospray ionization MS and tandem MS (triple quadrupole and hybrid quadrupole-orthogonal acceleration time of flight analyzers) to characterize MDA-, CR-, HX- and HNE-modified dG and nucleotide (3'- and 5'-monophosphate; 3',5'-bisphosphate) adducts. These data have been used to validate 32P-postlabeling methods for quantification of low level MDA-dG adducts formed in DNA of human and animal tissues. Availability of reliable methods for quantification of endogenous DNA damage in humans and animals is essential for determining unknown etiologies of cancer and for the assessment of cancer risks in humans.

Topics: Aldehydes; Chromatography, Liquid; Deoxyadenosines; Deoxyguanosine; DNA Adducts; Lipid Peroxidation; Malondialdehyde; Mass Spectrometry; Reproducibility of Results; Sensitivity and Specificity

4-Hydroxynonenal, a product of oxidative degradation of unsaturated lipids, is an endogenous reactive alpha,beta-unsaturated aldehyde with numerous biological activities. 4-Hydroxynonenal rapidly inactivated glutathione reductase in an NADPH-dependent reaction. Inactivation appears to involve the initial formation of an enzyme-inactivator complex, K(D) = 0.5 microM, followed by the inactivation reaction, k = 1.3 x 10(-2) min(-1). alpha,beta-Unsaturated aldehydes such as acrolein, crotonaldehyde, and cinnamaldehyde also inactivated glutathione reductase, although rates varied widely. Inactivation of glutathione reductase by alpha,beta-unsaturated aldehydes was followed by slower NADPH-independent reactions that led to formation of nonfluorescent cross-linked products, accompanied by loss of lysine and histidine residues. Other reactive endogenous aldehydes such as methylglyoxal, 3-deoxyglucosone, and xylosone inactivated glutathione reductase by an NADPH-independent mechanism, with methylglyoxal being the most reactive. However, 2-oxoaldehydes were much less effective than 4-hydroxynonenal. Inactivation of glutathione reductase by these 2-oxoaldehydes was followed by slower reactions that led to the formation of fluorescent cross-linked products over a period of several weeks. These changes were accompanied by loss of arginine residues. Thus, the sequence of events is different for inactivation and modification of glutathione reductase by alpha,beta-unsaturated aldehydes compared with 2-oxoaldehydes with respect to kinetics, NADPH requirements, fluorescence changes, and loss of amino acid residues. The ability of 4-hydroxynonenal at low concentrations to inactivate glutathione reductase, a central antioxidant enzyme, suggests that oxidative degradation of unsaturated lipids may initiate a positive feedback loop that enhances the potential for oxidative damage.

Topics: Acrolein; Aldehydes; Amino Acids; Deoxyglucose; Enzyme Activation; Glutathione Reductase; Ketoses; Pyruvaldehyde; Spectrometry, Fluorescence

In the present study the irreversible inhibition of human glutathione S-transferase P1-1 (GSTP1-1) by alpha, beta-unsaturated aldehydes and ketones was studied. When GSTP1-1 was incubated with a 50-fold molar excess of the aldehydes acrolein (ACR) and 4-hydroxy-2-nonenal (HNE) and the ketones curcumin (CUR) and ethacrynic acid (EA) at 22 degrees C, all of them inactivated GSTP1-1. The remaining activity after 4 h of incubation in all cases was lower than 10%. The aldehydes crotonaldehyde (CRA), cinnamaldehyde (CA) and trans-2-hexenal were found to inhibit GSTP1-1 only at a 5000-fold molar excess and even then, for example, for CA a higher remaining activity of 17% was observed. The same inhibition experiments were conducted with 3 mutants of GSTP1-1: the C47S and C101S mutants and the double mutant C47S/C101S. Remaining activity for C47S varied between +/- 40% for CRA, CA, CUR and HEX and +/- 80% for ACR, EA and HNE. For C101S it varied between 0 and 9% and for the double mutant C47S/C101S, activity after 4 h of incubation was variable. Again it varied between +/- 40% for CRA, CA, CUR and HEX and +/- 80% for ACR, EA and HNE. EA is known to react almost exclusively with cysteine 47. When [14C]EA was incubated with the GSTP1-1, modified by the alpha, beta-unsaturated carbonyl compounds, no [14C]EA was incorporated in the enzyme, indicating that in all cases this cysteine residue was one of the major targets. Since Michael addition with these reagents is known to be reversible, the results of incubation of the inactivated enzymes with an excess of glutathione (GSH) were determined. For all compounds, a restoration of the catalytic activity was observed. The results indicate that alpha, beta-unsaturated carbonyl derivatives inhibit GSTP1-1 irreversibly mainly by binding to cysteine residues of GSTP1-1, especially Cys-47, This means that some of these compounds (e.g. CUR) might modify GST activity in vivo when GSH concentrations are low by covalent binding to the enzyme.

Topics: Acrolein; Aldehydes; Curcumin; Cysteine Proteinase Inhibitors; Enzyme Inhibitors; Ethacrynic Acid; Glutathione S-Transferase pi; Glutathione Transferase; Humans; Isoenzymes; Ketones; Mutagenesis, Site-Directed

An important aspect of bacterial mutagenesis by several difunctional carbonyl compounds appears to be the induction of the SOS system. We tested the ability of a series of carbonyl compounds to induce expression of the SOS-regulated umu operon in Salmonella typhimurium TA1535/pSK1002. SOS-inducing potencies varied widely among the carbonyl compounds tested. 4-Hydroxynonenal, a product of lipid peroxidation, was the most potent SOS-inducer, with maximal induction observed at concentrations of 0.1-1 microM. Acrolein, crotonaldehyde and methacrolein induced little increase over background umu expression. Malondialdehyde, another product of lipid peroxidation, was a very weak SOS-inducer with a maximal response induced at a concentration of 28 mM. Substitution at the alpha-position of malondialdehyde, which abolishes frameshift mutagenicity, did not abolish SOS-inducing activity. Substitution of the hydroxyl group of malondialdehyde and alpha-methyl-malondialdehyde by a better leaving group (benzoyloxy) resulted in an approximately 250-fold higher SOS-inducing potency. Comparison of the present results to literature reports on bacterial mutagenicity indicates a poor correlation of the two properties between different classes of difunctional carbonyl compounds and even within the same class of difunctional carbonyl compounds.

Topics: Acrolein; Aldehydes; Lipid Peroxidation; Malondialdehyde; Mutagens; Operon; Salmonella typhimurium; SOS Response, Genetics

Topics: Acrolein; Aldehydes; Cell Membrane; Humans; In Vitro Techniques; Macrophages; Membrane Fluidity; Neutrophils; Sulfhydryl Compounds

alpha,beta-Unsaturated aldehydes are reactive compounds which are ubiquitous in the environment. This class of compounds has been tested for mutagenicity in Salmonella typhimurium by a number of groups who have obtained differing results. The present studies were undertaken to test the mutagenicity and toxicity of two novel alpha, beta-unsaturated aldehydes, specifically trans, trans-muconaldehyde and trans-4-hydroxynonenal, and to re-examine the mutagenicity of crotonaldehyde. Trans, trans-muconaldehyde is a newly found microsomal metabolite of benzene, and trans-4-hydroxynonenal is a toxic aldehyde formed endogenously during lipid peroxidation. Compounds were tested in S. typhimurium strain TA 100 using a 30-min liquid preincubation procedure. The present mutagenicity studies indicate that these alpha, beta-unsaturated aldehydes at first appear to be mutagenic, although only at concentrations which decrease survival counts, and result in a disappearance of the bacterial lawn. The colonies observed on mutagenicity test plates are not mutants but rather pin point survivors.

Topics: Aldehydes; Cell Survival; Mutagenicity Tests; Mutagens; Salmonella typhimurium; Structure-Activity Relationship