Molecular requirements for the mutagenicity of malondialdehyde and related acroleins.
Malondialdehyde, a product of lipid peroxidation and prostaglandin biosynthesis, is mutagenic in Salmonella. To determine the molecular requirements for its mutagenicity, we tested a series of beta-substituted acroleins in Salmonella typhimurium hisD3052 . Mutagenicity is dependent on the steric bulk of the substituent (revertants/mumol) at the beta position: beta- methoxyacrolein , 220; beta- ethoxyacrolein , 110; and beta- isobutoxyacrolein , 40. A good leaving group at the beta position substantially increases the mutagenic activity (revertants/mumol): beta-(p-nitrophenoxy)acrolein, 620; beta- benzoyloxyacrolein , 320; beta- chloroacrolein , 890; and di-gamma- oxopropenyl ether, 870. These data suggest that nucleophilic attack on the beta-carbon followed by elimination of the beta substituent is important for mutagenicity. Substitution of a methyl group at the alpha-carbon abolishes mutagenicity of these compounds. This effect can be explained by the lack of chemical reactivity of the alpha-methyl analogues toward oxygen or nitrogen nucleophiles. Propynal , which can add nucleophiles to generate a substituted acrolein, exhibits the highest mutagenicity (1370 revertants/mumol) in this series. The importance of the aldehyde functionality is suggested by the nonmutagenicity of propiolonitrile , ethyl propiolate , 4-benzoyloxy-3- buten -2-one, and 4-methoxy-3- buten -2-one. Aldehyde addition subsequent to the formation of the Michael adduct is, therefore, important for mutagenesis. An investigation of the toxicity of the present series indicates that toxicity and mutagenicity are independent events based on different chemical reactions.
D000171:Acrolein / Q000031:analogs & derivatives / Q000633:toxicity*; D000447:Aldehydes / Q000633:toxicity*; D000478:Alkylation; D000818:Animals; D001711:Biotransformation; D008314:Malonates / Q000633:toxicity*; D008315:Malondialdehyde / Q000633:toxicity*; D008862:Microsomes, Liver / Q000378:metabolism; D009152:Mutagenicity Tests; D009153:Mutagens; D009154:Mutation; D051381:Rats; D012486:Salmonella typhimurium / Q000187:drug effects; D013329:Structure-Activity Relationship
D000447:Aldehydes; D008314:Malonates; D009153:Mutagens; D008315:Malondialdehyde; D000171:Acrolein