PubMed · 3864730
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1985. Acrolein.. https://pubmed.ncbi.nlm.nih.gov/3864730/
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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.
We have previously shown that E-3-amino-1-phenyl-prop-1-ene (E-cinnamylamine) is readily oxidised by monoamine oxidase (MAO) type B from either rat or bovine liver (Williams et al. (1988), Biochem. J. 256, 411-415) in each case producing a non-linear progress curve which was attributed to inhibition by the reaction product E-cinnamaldehyde. We have now found that although this aldehyde inhibits MAO B competitively (Ki 0.017 mM) this cannot account for the inhibitory process, since during a 60 min incubation with the substrate (0.5 mM; Km, 0.074 mM) more than 95% inhibition of MAO B was observed and the concentration of aldehyde had reached approx. 0.025 mM. Inhibition was relieved either by dialysis or dilution of inhibited samples. The activity of MAO A from rat liver was largely unaffected by E-cinnamylamine. Oxidation of N-methyl-E-cinnamylamine and its Z-isomer by MAO B produced progress curves similar to that obtained with the primary amine, but in these cases inhibition was not reversed either by dilution or dialysis. Partition ratios for the pair of N-methyl isomers with bovine MAO B were calculated to be 1640 (E-isomer) and 1430 (Z-isomer). The time-dependent inhibition process for all three amines obeyed pseudo-first-order kinetics. A tritiated form of N-methyl-E-cinnamylamine, incubated with MAO B from bovine liver, resulted in incorporation of radioactivity into the enzyme. This labelling was stable to dialysis and to SDS-PAGE.
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.