(S)-Preferential detoxification of 4-hydroxy-2(E)-nonenal enantiomers by hepatic glutathione S-transferase isoforms in guinea-pigs and rats

Abstract

In guinea-pig liver cytosol, racemic 4-hydroxy-2(E)-nonenal (HNE), a reactive and highly toxic product released from biomembranes by lipid peroxidation, was detoxified (S)-preferentially by GSH conjugation mediated by glutathione S-transferases (GSTs) and (R)-preferentially by NAD(+)-dependent oxidation mediated by aldehyde dehydrogenase (ALDH). The GST-mediated detoxification of the HNE enantiomers proceeded at much higher rates than that mediated by ALDH in guinea-pig liver cytosol. All the major guinea-pig GSTs, A1-1, M1-1, M1-2 and M1-3*, isolated from guinea-pig liver cytosol also catalysed the (S)-preferential conjugation of the HNE enantiomers. The liver and other major tissues of guinea-pigs had no immunologically detectable level of a putative GSTA4-4 orthologue, which exists as a minor GST protein in rat, mouse and human livers and exhibits extremely high catalytic activity towards HNE. All the hepatic rat GSTs, A1-1(2), A1-3, A4-4, M1-1, M1-2 and M2-2, also catalysed the (S)-preferential conjugation of HNE enantiomers.

Polymorphisms of the glutathione S-transferases mu-1 (GSTM1) and theta-1 (GSTT1) and the risk of advanced alcoholic liver disease

“…The highest affinity has been found for a new alpha class enzyme, GST A4-4 [22]. The expression of this isoform in liver tissue is still under discussion [23,24], whereas the expression of GSTA1, GSTM1 and GSTT1 has been fully confirmed [7,25,26]. Classically, it has been considered that GSTA1 possess the highest catalytic efficiency for 4-hydroxy nonenal neutralization, but the gene coding for the GSTA1 enzyme is highly conserved in man, no gene deletions or enzyme-inactivating mutations have been described so far, and the detected SNPs are located at the promoter region, or are silent, and their functional significance is under discussion [27 Á/ 30].…”

Effects of Local Heart Irradiation in a Glutathione S-Transferase Alpha 4-Null Mouse Model

“…Glutathione S-transferase alpha 4 (GSTA4-4) is one of the enzymes responsible for the removal of 4-hydroxynonenal (4-HNE), an electrophilic product of lipid peroxidation formed in cellular membranes during oxidative stress, by conjugating it with glutathione (1). We have previously generated and characterized Gsta4 -null mice on a 129/Sv and a C57BL genetic background (2, 3).…”

Quantification of trans-4-hydroxy-2-nonenal enantiomers and metabolites by LC–ESI-MS/MS

“…The targets of HNE adduction and the pathways of HNE metabolism are influenced by the stereochemistry of HNE [16][17][18]. HNE possesses a chiral center at C4 (Fig.…”

“…1). Hepatic glutathione-(S)-transferases preferentially conjugate (S)-HNE to GSH to form (S)-(4-hydroxy-1-oxononan-3-yl) glutathione (GSHNE) [16,17]. In rat brain mitochondria, (R)-HNE is preferentially metabolized over (S)-HNE to HNEAcid by aldehyde dehydrogenases (ALDHs) [19,20].…”