THE TOXICITY AND DETOXIFICATION OF α, β-UNSATURATED ALDEHYDES

Abstract

trans-Cinnamaldehyde (CA) which is an α, β-unsaturated aldehyde, one of the most widely used flavoring agents in the world, is mutagenic in Salmonella, and is an inducer of the skin inflammation in rodents and in the human. In rat liver cytosol, the glutathione (GSH) conjugation of CA proceeded at a much higher rate than did its NADH-dependent reduction. CA was found to be a good substrate for the rat (r) liver class Mu GSH S-transferases (rGSTs) M2-2, M1-2, and MI-1 in decreasing order. The glycolytic enzyme, glyceraldehyde-3-phosphate dehydrogenase (GAPDH), was irreversibly and highly 4(S)-selectively inactivated by the enantiomers of racemic 4-hydroxy2(E)-nonenal (4-HNE), a reactive product released from biomembranes by lipid peroxidation in cells. IC50 of 4(R)HNE for GAPDH was 3.6-fold higher than that of the 4(S)-enantiomer. In rat liver cytosol, the 4-HNE was detoxified highly 4(S)-selectively by GSH conjugation and 4(R)-selectively by NADH-dependent reduction mediated by alcohol dehydrogenase (ADH). In the cytosol, however, the GSH conjugation of 4(R)-HNE proceeded at a much higher rate than did its ADH-mediated reduction. The minor GST isoform, A4-4, in the rat liver played a major role in the cytosolic (S)-selective GSH conjugation. The catalytic efficiency, kcat/Km, of purified rGSTA4-4 was 4-fold higher for 4(S)-HNE than for 4(R)-HNE. Because of its much smaller Km than that of 4(R)-HNE, 4(S)-HNE was preferentially detoxified by rGSTA4-4 when racemic 4-HNE was used as a substrate.