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At least 19 recordsLinked to original sources
PubMed1992

Acrolein initiates rat urinary bladder carcinogenesis.

Acrolein, a reactive, alpha,beta-unsaturated aldehyde which is ubiquitous in the environment, forms DNA adducts, is mutagenic, and is teratogenic. However, studies have not indicated a carcinogenic effect in rodent bioassays. Since it is present in cigarette smoke and is the toxic metabolite of cyclophosphamide with respect to the urinary tract, we investigated the possibility that acrolein might have carcinogenic activity toward the rat urinary bladder. We also evaluated whether it possessed initiating and/or promoting activity. To evaluate initiating activity, acrolein was administered at a dose of 2 mg/kg i.p. twice a week for 6 weeks followed by uracil as 3% of the diet for 20 weeks and then control diet for 6 weeks. N-[4-(5-Nitro-2-furyl)-2-thiazolyl]formamide (FANFT) as 0.2% of the diet followed by uracil was used as a positive control, and a negative control group was administered solvent control (water) i.p. during the 6-week initiation period followed by uracil. Acrolein followed by uracil produced an incidence of 18 of 30 rats (60%) with papilloma compared to 8 of 30 rats (27%) treated with solvent control followed by uracil. FANFT followed by uracil produced an incidence of 70% carcinomas and 30% papillomas, clearly indicating that it is a much more potent initiating agent than acrolein. Acrolein for 6 weeks followed by control diet produced no tumors. To evaluate promoting activity, groups of rats were fed FANFT for 6 weeks followed by acrolein. Acrolein administered during the initial 6 weeks and continued for the second phase of the experiment (to evaluate complete carcinogenic activity) resulted in severe toxicity. Administration of acrolein had to be terminated after 21 weeks of the experiment. The animals were maintained for 53 weeks of the experiment without further chemical treatment, and there was no evidence of papilloma or carcinoma development. This study clearly indicates that acrolein has initiating activity for the urinary bladder when administered by i.p. injection to the male F344 rat, but toxicity precluded evaluation of its promoting or complete carcinogenic activity.

Acrolein↗
PubMed1992

The acrolein cytotoxicity and cytoprotective action of alpha-tocopherol in primary cultured rat hepatocytes.

The influence of acrolein on hepatocytes and the effect of alpha-tocopherol on acrolein cytotoxicity were investigated using primary cultured rat hepatocytes. Hepatocellular injury was dependent on both acrolein concentration in medium and on duration of exposure. Treatment of hepatocytes with 100 microM acrolein resulted in a marked loss of cellular glutathione (GSH) within 15 min, gradual accumulation of cellular lipid peroxide (LPO) and subsequent lactate dehydrogenase (LDH) leakage in the medium from 3 hr after exposure to acrolein. Cellular GSH peroxidase (GSH-Px) activity at 2 hr was significantly decreased. Electron microscopic examination on hepatocytes at 8 hr revealed a marked swelling of mitochondria and ruptures of the plasma membrane. Simultaneous treatment with 100 microM acrolein and 20 microM alpha-tocopherol did not prevent the loss of cellular GSH, though it prevented the LPO accumulation and the LDH leakage. The decrease of cellular GSH-Px activity with acrolein treatment was not mitigated by co-treatment with alpha-tocopherol. Ultrastructural alterations of hepatocytes induced by acrolein were minimized by co-treatment with alpha-tocopherol. In conclusion, acute loss of GSH and GSH-Px may increase cellular LPO and lead to hepatocellular injury, though suppression of cellular LPO accumulation by alpha-tocopherol can prevent the hepatocellular injury, even under condition of lack of GSH and GSH-Px.

Acrolein↗
PubMed1992

Nephrotoxicity of the 1:1 acrolein-glutathione adduct in the rat.

Previous metabolic studies in rats have suggested in vivo formation of the acrolein-glutathione (acrolein-GSH) adduct following administration of the highly reactive alpha, beta-unsaturated aldehyde acrolein. Early studies by several investigators demonstrated that similar compounds such as alpha, beta-unsaturated aldehyde-cysteine adducts have toxic (carcinostatic) activity against Ehrlich ascites tumor cells implanted in mice. The current studies investigated the in vivo toxicity associated with the acrolein-GSH adduct in the male Sprague-Dawley rat. The 1:1 acrolein-GSH adduct was synthesized and characterized by physical-chemical methods. Rats given the acrolein-GSH adduct intravenously at 0.5 or 1 mmol/kg developed nephrotoxicity characterized by glucosuria, proteinuria, elevation in serum urea nitrogen, and gross and histologic changes of the kidney. The toxicity was not affected by pretreatment of rats with pyrazole, an alcohol dehydrogenase inhibitor; disulfiram, an inhibitor of aldehyde dehydrogenases; or probenecid, a renal organic anion transport inhibitor. Administration of a similar but nonaldehydic glutathione conjugate, S-n-propylglutathione, did not result in nephrotoxicity in the rat. The nephrotoxicity induced by the acrolein-GSH adduct was inhibited by acivicin, a gamma-glutamyl-transpeptidase inhibitor. These results indicate that the acrolein-GSH adduct requires processing through the first step of the renal mercapturic acid synthesis pathway to be activated to a toxic species.

Acrolein↗
PubMed1992

Acute effects of acrolein on breathing: role of vagal bronchopulmonary afferents.

Spontaneous inhalation of acrolein vapor (350 ppm, 1 ml/100 g body wt) elicited an immediate and transient inhibitory effect on breathing in anesthetized rats, characterized by a prolongation of expiratory duration and accompanied by a bradycardia; ventilation was reduced by 47 +/- 6%, which returned to baseline after three to seven breaths. When both vagi were cooled to 6.6 +/- 0.1 degrees C, the reflex apneic response to lung inflation was completely abolished but the bradypneic response to acrolein was not affected. After perineural capsaicin treatment of both cervical vagi to selectively block the capsaicin-sensitive C-fiber afferents, acrolein no longer evoked an inhibitory effect on breathing; conversely, an augmented inspiration was consistently elicited with the first breath of acrolein inhalation, which was subsequently abolished by cooling both vagi to 6.5 degrees C. The inhibitory effect of inhaling acrolein at a lower concentration (200 ppm) was not detectable, whereas that of a higher concentration (600 ppm) was more intense and prolonged. All these responses were completely eliminated by bilateral vagotomy. These results suggest that inhaled acrolein activated both vagal C-fiber endings and rapidly adapting irritant receptors in the airways, but the acrolein-induced inhibitory effect on breathing was elicited primarily by the C-fiber afferent stimulation.

Acrolein↗
PubMed1976

Studies on the in vivo formation of acrolein: 3-hydroxy-propylmercapturic acid as an index of cyclophosphamide (NSC-26271) activation.

3-Hydroxypropylmercapturic acid (MCA) has been quantitatively determined in the urine of rats given cyclophosphamide (CP), related antineoplastic agents, allyl alcohol, or acrolein, with a simple procedure involving the use of an amino-acid analyzer. Male rats (300-400 g) injected with CP (50mg [179.1 mumols]/kg of body weight) excreted 16.7 mumols of MCA/kg in their 24-hour urine. Equivalent amounts of isophosphamide produced 9.0; triphosphamide, 16.1; ASTA-5607, 7.2; ASTA-5122, 4.1; and cytoxyl alcohol, 0.4mumols of MCA/kg. From allyl alcohol and acrolein, 26.3 and 19.7 mumols of MCA/kg were obtained respectively. MCA values were directly proportional to drug dose levels. Since acrolein and phosphorodiamidic acid mustard are the toxic decomposition products of aldophosphamide, and acrolein conjugation appears to be the first step for MCA formation values for MCA would reflect active CP levels. The in vitro interaction of acrolein with glutathione, other sulfhydryl compounds, and a few amino acids at concentrations of 0.15 mumols/ml was also studied. The decrease of acrolein's main absorption peak at 209 nm was used to follow its reaction rate. The faster interactions observed were with the sulfhydryl compounds, where a 50% decrease of absorption in interactions with glutathione and cysteine (at pH 7.4 and 23 degrees C) took place in 111 and 30 seconds respectively. Incubation of these adducts at 37 degrees C and 100 degrees C generated acrolein with a maximum recovery yield of 83% at 100 degrees C. Five patients given 1 g of CP iv excreted 6.4-50 mumols of MCA in their urine in 6 hours.

Acetylcysteine↗
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↗
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↗
PubMed1978

A solid sorbent personal sampling method for the determination of acrolein in air.

A personal air sampling method, using activated carbon with subsequent analysis by gas chromatography, has been developed for acrolein in the 0.05 to 5 ppm (parts per million) range for a five liter air sample. The sensitivity is 0.25 microgram (microgram) of acrolein. This first known viable method for acrolein using a solid adsorbent was made possible by the discovery that acrolein can be adsorbed on, and recovered from, hydroquinone-treated carbon with efficiencies as high as 90 percent. Samples must be analyzed the same day or frozen and analyzed within five days. Airborne contaminants possibly present in the acrolein production area do not interfere with the analysis.

Acrolein↗
PubMed1977

Adverse effect of a cigarette smoke component, acrolein, on pulmonary antibacterial defenses and on viral-bacterial interactions in the lung.

Intrapulmonary antibacterial activity in normal mice and mice with viral pneumonia was determined after continous exposure to the pure tobacco smoke component, acrolein. After inhalation challenge with Staphylococcus aureus and Proteus mirabilis, exposure to 1 to 2 ppm of acrolein significantly suppressed the intrapulmonary killing of the organisms in normal mice compared to control mice not exposed to acrolein. Sendai virus pneumonia depressed pulmonary antibacterial defenses in a virus dose-related fashion. Exposure of the mice infected with virus to acrolein resulted in a further suppression of intrapulmonary bacterial killing to the extent that, in most instances, the bacteria proliferated in the lungs. These data demonstrate that the cigarette smoke component, acrolein, not only depresses pulmonary bactericidal activity, but can also act as a stressor in aggravating an underlying disease process, resulting in an additional impairment of pulmonary antibacterial defenses.

Acrolein↗
PubMed1976

Acrolein as a fixative for enzyme cytochemistry.

Since acrolein can penetrate more quickly and deeply into tissue blocks than glutaraldehyde, the possibility of the use of this aldehyde as a prefixative in enzyme cytochemistry was reinvestigated. At low concentrations, acrolein preserves the activities of the enzymes investigated, including those of glucose-6-phosphatase, which is known as one of the most vulnerable to aldehyde fixation; thus, acrolein is usable in enzyme ultracytochemistry. Enzyme activities are also preserved in tissues fixed with acrolein and glutaraldehyde combined. The rapid penetration of acrolein enables fixation in larger tissue blocks and provides greater freedom in specimen selection, especially important advantages when encountering heterogeneous materials as in pathology.

Acid Phosphatase↗
PubMed1977

Critical analysis of the use of the acrolein-Schiff method as a possible DNA reaction.

Histophotometric examination was carried out on nuclei of lymphocytes in human peripheral blood, which were subjected to various tests in order to assess the acrolein-Schiff method as a possible DNA specific reaction, in comparison with the traditional Feulgen reaction. Special attention was paid to the degree of difference between responses attributable to a direct Schiff reaction obtained in the fraction of nuclear proteins after treatment with acrolein. From the results obtained it appears that an acrolein-Schiff reaction, following extraction of proteins, may be considered a qualitative reaction for DNA. Our findings also show that there is no relationship between the degree of response to the acrolein-Schiff reaction and that the Feulgen reaction, which is to be expected in view of the different mechanisms of the two reactions.

Acrolein↗
PubMed1976

Some aspects of the persistence and fate of acrolein herbicide in water.

Experimental data for the decay of acrolein approximated first order kinetics. The reaction continued to completion in local waters but in buffered solution (pH 5.1-8.6) an equilibrium was reached after reaction of about 92% of the acrolein. It is proposed that data presented on the effects of pH on decay of acrolein may be used as a conservative estimate of dissipation rates in water where non-target organisms are at risk. In flowing water in two channels the 8 to 10 fold discrepancy between observed and predicted rates of dissipation was attributed to major losses in volatilization and adsorption. A relatively non-volatile reaction product (which gave a positive reaction with dinitrophenylhydrazine) accumulated initially but dissipated rapidly, probably by microbiological processes, when acrolein concentrations fell below about 2 to 3 ppm.

Acrolein↗
PubMed1992

Reproductive study of acrolein on two generations of rats.

Four groups of 30 male and 30 female rats were intubated with 70 daily doses of acrolein at levels of 0, 1, 3, or 6 mg/kg in a dosing volume of 5 ml/kg. Rats within each dosing group (F0 generation) were then assigned to a 21-day period of cohabitation and dosing for females continued through cohabitation gestation and lactation. Males were euthanized after cohabitation. F1 generation rats were chosen from pups, and a similar pretreatment, cohabitation, gestation, and lactation regimen was accomplished resulting in F2 generation pups. Reproductive parameters, body weights, food consumption, and clinical signs were recorded and necropsies were carried out on all treated animals. Histopathologic exams were accomplished on selected reproductive tissues. In addition, gross lesions, target tissues, stomachs, and lungs were examined. For the most part, reproductive parameters were unaffected by acrolein treatment with the exception of reduced pup weights in the F1 generation pups at the high-dose level (6 mg/kg/day). Gastric lesions were noted consistently in high-dose animals and some mid-dose (3 mg/kg/day) rats. Erosions of glandular mucosa and hyperplasia/hyperkeratosis of the forestomach were the most frequent stomach lesions observed. Effects on body weight gains were noted frequently for the high-dose animals and achieved statistical significance in the mid-dose animals on several occasions. Mortality in all high-dose animals was elevated relative to control animals. Acrolein, therefore, cannot be considered a selective reproductive toxin in the rat, but does produce toxicological effects down to a dosing level of 3 mg/kg/day.

Acrolein↗
PubMed1992

Cyclophosphamide and its metabolite acrolein. Some studies on their porphyrinogenic action in 17 day old chick embryo.

1. Some studies of cyclophosphamide (CP) and its metabolite acrolein in chick embryo liver were carried out in order to investigate the mechanism of the porphyrinogenic action of CP. 2. In vitro and in vivo studies revealed that CP induced but did not activate delta-aminolaevulinic acid (ALA) synthase. 3. Pretreatments with phenobarbital (PB) or SKF-525A did not modify ALA-synthase induction produced by CP. 4. Acrolein administration neither induced ALA-synthase activity nor increased cytochrome P-450 content or led to hepatic porphyrin accumulation. 5. Time course induction of cytochrome P-450 content after administration of CP or PB was similar. 6. The results obtained would indicate that CP is a strong inducer of both ALA-synthase activity and microsomal cytochrome P-450 content in liver of 17 day-old chick embryos and that its porphyrinogenic activity is not mediated by its metabolite acrolein.

5-Aminolevulinate Synthetase↗
PubMed1990

Acrolein depletes the neuropeptides CGRP and substance P in sensory nerves in rat respiratory tract.

The mammalian respiratory tract is densely innervated by autonomic and sensory nerves around airways and blood vessels. Subsets of these nerves contain a number of putative neurotransmitter peptides, such as substance P and calcitonin gene-related peptide (CGRP) in sensory nerves and vasoactive intestinal polypeptide (VIP), possibly serving autonomic functions. CGRP is also found in endocrine cells in rat airway epithelium. These peptides are all pharmacologically potent effectors of bronchial and vascular smooth muscle and bronchial secretion. Their functions in vivo are less well established. We have therefore examined the effects of inhaled acrolein, a sensory irritant, on three pulmonary neuropeptides: CGRP, substance P, and VIP. Groups of rats (n = 3 each) were exposed for 10 min to acrolein in air (Ct = 510, 1858, and 5693 mg.min/m3) or to air alone. Fifteen minutes later they were killed (pentabarbitone IP) and their respiratory tracts were dissected and fixed in 0.4% p-benzoquinone solution. Cryostat sections were stained by indirect immunofluorescence for a general nerve marker (PGP 9.5) and neuropeptides. The acrolein-treated animals had a dose-related decrease in tracheal substance P- and CGRP-immunoreactive nerve fibers compared with controls. No change was seen in total nerve fiber distribution and number (PGP 9.5) or VIP immunoreactivity, nor in CGRP-immunoreactive epithelial endocrine cells. It is concluded that the rat tracheal peptidergic nerves are a sensitive indicator of inhaled irritant substances. Their reduced immunoreactivity may be because of a release of sensory neuropeptides that could play a role in the physiological response to irritant or toxic compounds.

Acrolein↗
PubMed1979

Acrolein, the causative factor of urotoxic side-effects of cyclophosphamide, ifosfamide, trofosfamide and sufosfamide.

The urotoxicity of oxazaphosphorine cytostatics is not based on their alkylating activity but on the presence of acrolein, which is spontaneously formed in the urine from the primary metabolites eliminated via the kidneys. Thus, acrolein proved to be the causative factor in the urotoxicity of oxazaphosphorines. The mechanism of action of the uroprotector sodium 2-mercaptoethane-sulfonate (mesnum, Mitexan) is mainly based on the formation of a non-toxic additive compound with acrolein.

Acrolein↗
PubMedDate not supplied

[Effects in the rat of a weak dose of acrolein inhaled continuously].

The results of an experiment on 173 S. P. F. rats inhaling 0.55 ppm of acrolein, compared to 173 control rats, are reported. In what concerns the respiratory apparatus, this dose of acrolein affects its defense mechanisms, leading to a greater susceptibility to the airborne Salmonella enteritidis infection, compared to the control group. These phenomena disappear spontaneously when intoxication is prolonged more than three weeks. On the contrary, the general toxic action, manifesting itself through diminished weight growth and under-nourishment, compared to control group, lasts as long as intoxication and disappears only after acrolein inhalation has stopped. These results are discussed.

Acid Phosphatase↗
PubMed1992

Mutagenicity of beta-alkyl substituted acrolein congeners in the Salmonella typhimurium strain TA100 and genotoxicity testing in the SOS chromotest.

The beta-alkyl substituted acrolein congeners crotonaldehyde, trans-2-pentenal, trans-2-hexenal, 2,4-hexadienal, and trans-2-heptenal were clearly mutagenic in a slightly modified preincubation Ames test with Salmonella typhimurium TA100 with and without S9 mix using a threefold bacterial cell density and a 90-min preincubation time, whereas trans-cis-2,6-nonadienal did not show any mutagenic activity. The greatest impediment to adequate mutagenicity testing of these compounds is their toxicity toward bacteria. Within the congener family tested, toxicity increases as a function of both chain length and lipophilicity, and it becomes more and more difficult to demonstrate mutagenicity. Mutagenicity decreases with increasing chain length. This effect may be explained by increasing toxicity. The effect of S9 mix seems to be mostly nonenzymatic detoxication by nonspecific scavanger protection of bacterial cytotoxicity. No indication could be found that bioactivation plays a role in S9-mediated reduction of bacterial cytotoxicity. Although positive mutagenic outcomes could be obtained with the SOS chromotest for other alpha, beta-unsaturated carbonyl compounds, these acrolein congeners were not genotoxic in this test, most probably because they are toxic for the Escherichia coli bacteria PQ37 and PQ243.

Acrolein↗