4-Hydroxy-2(E)-nonenal enantiomers: (S)-selective inactivation of glyceraldehyde-3-phosphate dehydrogenase and detoxification by rat glutathione S-transferase A4-4.
The glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase was irreversibly and (S)-selectively inactivated by the enantiomers of racemic 4-hydroxy-2(E)-nonenal (HNE), a reactive product released from biomembranes by lipid peroxidation in cells. Rates of the enzyme inactivations were 1.7, 3.0, and 6.0 M(-1).s(-1) for (R)-, racemic and (S)-HNEs respectively. In rat liver cytosol the HNE was detoxified 2.5-fold more (S)-selectively by GSH conjugation and 2. 4-fold more (R)-selectively by NADH-dependent reduction mediated by alcohol dehydrogenase (ADH) than the opposite enantiomers. However, in the cytosol the GSH conjugation of (R)-HNE proceeded at a much higher rate than did its ADH-mediated reduction. The minor glutathione S-transferase (GST) isoform, A4-4, in the rat (r) liver had a major role in the cytosolic (S)-selective GSH conjugation. The catalytic efficiency, k(cat)/K(m), of purified rGSTA4-4 was 4-fold higher for (S)-HNE than for (R)-HNE; the K(m) was 3-fold higher for (R)-HNE than for (S)-HNE. (S)-HNE was preferentially detoxified to (R)-HNE by rGSTA4-4 when racemic HNE was used as a substrate.
Hiratsuka
A
A
Department of Drug Metabolism and Molecular Toxicology, School of Pharmacy, Tokyo University of Pharmacy and Life Science, Hachioji-shi, Tokyo 192-0392, Japan.
Hirose
K
K
Saito
H
H
Watabe
T
T
D000447:Aldehydes / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D017931:DNA Primers; D005982:Glutathione Transferase / Q000378:metabolism*; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006019:Glycolysis; D008099:Liver / Q000201:enzymology; D008297:Male; D010084:Oxidation-Reduction; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000378:metabolism; D013237:Stereoisomerism
D000447:Aldehydes; D017931:DNA Primers; D011994:Recombinant Proteins; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases; D005982:Glutathione Transferase; C027576:4-hydroxy-2-nonenal