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

Hiratsuka, Akira; Tobita, Kouichi; Saito, Hiroshi; Sakamoto, Yasuhiro; Nakano, Hiroaki; Ogura, K.; Nishiyama, Takahito; Watabe, Tadashi

doi:10.1042/bj3550237

Cited by 19 publications

(10 citation statements)

References 42 publications

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“…However, the total activity of GSTs in the liver did not differ significantly between the control and DHA-fed groups (Table 2). Ålin et al [34] and Hiratsuka et al [35] reported that GSTA4-4, which present as a very minor GST protein in rat liver, exhibited extremely high catalytic activity towards 4-HNE. When GSTs in rat liver were separated by the chromatography on DEAE-cellulose column, GST A4-4 (also called GST 8-8) activity (60 µmol/min) was much lower than other GSTs activity (4460 µmol/min) [34].…”

Section: Discussionmentioning

confidence: 99%

Docosahexaenoic Acid-Induced Lipid Peroxidation and Urinary Excretion of Mercapturic Acid in Rats

Sekine¹,

Kubo²,

Tadokoro³

et al. 2006

J. Clin. Biochem. Nutr.

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Summary We hypothesized a suppressive mechanism for dietary docosahexaenoic acid (DHA)-induced tissue lipid peroxidation in which the degradation products, especially aldehydic compounds, are conjugated with glutathione (GSH) through catalysis by glutathione S-transferases (GSTs), and then excreted into urine as mercapturic acids. Sprague-Dawley rats were fed a diet containing DHA (8.4 % of total energy) for 31 days. Lipid peroxides in the liver and kidney, liver GST and urinary excretion of mercapturic acid were measured. The lipid peroxide levels in the liver and kidney except the liver aldehydic compounds were higher, and the urinary excretion of mercapturic acid also tended to be higher in the DHA-fed rats although the activity of GST was not increased after DHA intake. We presume from our results that a proportion of the lipid peroxidation-derived aldehydic degradation products might be excreted into urine as mercapturic acid after intake of DHA, thus suppressing the accumulation of aldehydic products in tissues, particularly in the liver.

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Section: Discussionmentioning

confidence: 99%

Docosahexaenoic Acid-Induced Lipid Peroxidation and Urinary Excretion of Mercapturic Acid in Rats

Sekine¹,

Kubo²,

Tadokoro³

et al. 2006

J. Clin. Biochem. Nutr.

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“…The alphaand Mu-class rat GSTs catalyze GS-HNE preferentially. 40) Of the Mu-class rat GSTs, M2-2 is the most efficient. 40) However, there was no significant change in the expression of GST M2 mRNA (Fig.…”

Section: Discussionmentioning

confidence: 99%

Induction of Multidrug Resistance-Associated Protein MRP3 in the Liver of Rats Fed with Docosahexaenoic Acid

Kubo

Sekine²,

Saito³

2006

Bioscience, Biotechnology, and Biochemistry

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“…Furthermore, Hiratsuka et al (32) demonstrated that the S-HNE enantiomer irreversibly inactivated rabbit glyceraldehyde-3-phosphate dehydrogenase at a greater rate than R-HNE. They also found a stereoselective consumption of substrate by rat GSTA4-4 in the order of S-HNE Ͼ racemic HNE Ͼ R-HNE (33), whereas a separate study by Boon et al (28) speculated that product stereoselectivity on behalf of GSTs is one potential explanation for the unequal distribution of GSHNE diastereomers observed in rat liver cytosol. Chirality has also been implicated as an important factor in other enzymes, such as aldehyde-dehydrogenase and aldo-keto reductases, that can also contribute to HNE metabolism and subsequent biotransformations of GSHNE (34 -36).…”

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confidence: 96%

The Stereochemical Course of 4-Hydroxy-2-nonenal Metabolism by Glutathione S-Transferases

Balogh

Roberts

Shireman

et al. 2008

Journal of Biological Chemistry

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4-Hydroxy-2-nonenal (HNE) is a toxic aldehyde generated during lipid peroxidation and has been implicated in a variety of pathological states associated with oxidative stress. Glutathione S-transferase (GST) A4-4 is recognized as one of the predominant enzymes responsible for the metabolism of HNE. However, substrate and product stereoselectivity remain to be fully explored. The results from a product formation assay indicate that hGSTA4-4 exhibits a modest preference for the biotransformation of S-HNE in the presence of both enantiomers. Liquid chromatography mass spectrometry analyses using the racemic and enantioisomeric HNE substrates explicitly demonstrate that hGSTA4-4 conjugates glutathione to both HNE enantiomers in a completely stereoselective manner that is not maintained in the spontaneous reaction. Compared with other hGST isoforms, hGSTA4-4 shows the highest degree of stereoselectivity. NMR experiments in combination with simulated annealing structure determinations enabled the determination of stereochemical configurations for the GSHNE diastereomers and are consistent with an hGSTA4-4-catalyzed nucleophilic attack that produces only the S-configuration at the site of conjugation, regardless of substrate chirality. In total these results indicate that hGSTA4-4 exhibits an intriguing combination of low substrate stereoselectivity with strict product stereoselectivity. This behavior allows for the detoxification of both HNE enantiomers while generating only a select set of GSHNE diastereomers with potential stereochemical implications concerning their effects and fates in biological tissues.Stereochemical configuration is a fundamental aspect of molecular structure, and the functional consequences of dynamic stereochemistry in biology are well established (1-6). Substrate stereoselectivity may occur in enzyme-mediated catalysis by virtue of the innate asymmetry of the active site. Product stereoselectivity may also arise when new chiral centers are introduced during an enzymatic reaction, because enzymes may specifically stabilize only one of the possible transition states for a given reaction. Stereoselective metabolism of both xenobiotic and endogenous molecules is a well recognized phenomenon that reflects this underlying chiral recognition process. To the extent that stereochemically distinct substrates and products have different biological effects, it is essential to define the stereochemical course of enzymatic reactions.Among the molecules generated endogenously from the degradation of polyunsaturated fatty acids during lipid peroxidation, the unsaturated aldehyde 4-hydroxy-2-nonenal (HNE) 2 has been implicated in a variety of pathological states associated with the deleterious consequences of oxidative stress, including atherosclerosis, diabetes, Alzheimer disease, and Parkinson disease (7-11). HNE has been proposed to exert a number of toxicological effects via its electrophilic ␣,␤-unsaturated carbonyl moiety that can react through additions with nucleophiles such as cysteine, histidine, a...

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

Cited by 19 publications

References 42 publications

Docosahexaenoic Acid-Induced Lipid Peroxidation and Urinary Excretion of Mercapturic Acid in Rats

Docosahexaenoic Acid-Induced Lipid Peroxidation and Urinary Excretion of Mercapturic Acid in Rats

Induction of Multidrug Resistance-Associated Protein MRP3 in the Liver of Rats Fed with Docosahexaenoic Acid

The Stereochemical Course of 4-Hydroxy-2-nonenal Metabolism by Glutathione S-Transferases

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