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Molecular Requirements for the Mutagenicity of Malondialdehyde and Related Acroleins¹

Department of Chemistry, Wayne State University Detroit, Michigan 48202

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 ß-substituted acroleins in Salmonella typhimurium hisD3052. Mutagenicity is dependent on the steric bulk of the substituent (revertants/µmol) at the ß position: ß-methoxyacrolein, 220; ß-ethoxyacrolein, 110; and ß-isobutoxyacrolein, 40. A good leaving group at the ß position substantially increases the mutagenic activity (revertants/µmol): ß-(p-nitrophenoxy)acrolein, 620; ß-benzoyloxyacrolein, 320; ß-chloroacrolein, 890; and di--oxopropenyl ether, 870. These data suggest that nucleophilic attack on the ß-carbon followed by elimination of the ß substituent is important for mutagenicity. Substitution of a methyl group at the -carbon abolishes mutagenicity of these compounds. This effect can be explained by the lack of chemical reactivity of the -methyl analogues toward oxygen or nitrogen nucleophiles. Propynal, which can add nucleophiles to generate a substituted acrolein, exhibits the highest mutagenicity (1370 revertants/µmol) in this series. The importance of the aldehyde functionality is suggested by the nonmutagenicity of propiolonitrile, ethylpropiolate, 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.

¹ This work was supported by Research Grant CA 22206 from the National Cancer Institute.

² Recipient of an American Cancer Society Faculty Research Award (FRA 243). To whom requests for reprints should be addressed.

Received 12/16/83. Accepted 4/ 3/84.

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