Interactions of glutathione transferases with 4-hydroxynonenal

Abstract

Electrophilic products of lipid peroxidation are important contributors to the progression of several pathological states. The prototypical α,β–unsaturated aldehyde, 4-hydroxynonenal (HNE), triggers cellular events associated with oxidative stress, which can be curtailed by the glutathione-dependent elimination of HNE. The glutathione transferases (GSTs) are a major determinate of the intracellular concentration of HNE and can influence susceptibility to toxic effects, particularly when HNE and GST levels are altered in disease states. In this article, we provide a brief summary of the cellular effects of HNE, followed by a review of its GST-catalyzed detoxification, with an emphasis on the structural attributes that play an important role in the interactions with alpha-class GSTs. Some of the key determining characteristics that impart high alkenal activity reside in the unique C-terminal interactions of the GSTA4-4 enzyme. Studies encompassing both kinetic and structural analyses of related isoforms will be highlighted, with additional attention to stereochemical aspects that demonstrate the capacity of GSTA4-4 to detoxify both enantiomers of the biologically relevant racemic mixture while generating a select set of diastereomeric products with subsequent implications. A summary of the literature that examines the interplay between GSTs and HNE in model systems relevant to oxidative stress will also be discussed to demonstrate the magnitude of importance of GSTs in the overall detoxification scheme.

Chemistry and analysis of HNE and other prominent carbonyl-containing lipid oxidation compounds

“…It is important to bear in mind that as well as reacting with macromolecules, free aldehydes may be metabolized and detoxified, so analysis of the metabolite may represent a good approach to detecting formation of the aldehyde in vivo. It is well known that HNE can be detoxified by conjugation to glutathione, catalysed by glutathione-S-transferases [94], and metabolized further to yield 1,4-dihydroxynonane-mercapturic acid, which can be detected in the urine together with other metabolites [95]. Trans,trans-2,4-decadienal (tt-DDE), a lipid peroxidation product of linoleic acid, can be oxidized to the two metabolites 2,4-decadienoic acid and cysteine-conjugated 2,4-decadien-1-ol.…”

Global Deletion of Glutathione S-Transferase A4 Exacerbates Developmental Nonalcoholic Steatohepatitis

“…8 Gsta4 is a detoxification enzyme that eliminates reactive electrophilic a,b unsaturated aldehydes, such as the lipid peroxidation product 4-hydroxynonenal (4-Hne). 9 We demonstrated that these dKO mice had enhanced hepatic Hne protein adducts, circulating autoantibodies against lipid peroxidation product-adducted proteins, necroinflammatory injury, stellate cell activation, and matrix remodeling than either wild-type mice or mice with knockout of either gene alone when fed chronically Data are expressed as means AE SEM. Total liver pathology was assessed in hematoxylin and eosinestained sections by a veterinary pathologist, as described in Materials and Methods.…”

Increased 4-hydroxynonenal protein adducts in male GSTA4–4/PPAR-α double knockout mice enhance injury during early stages of alcoholic liver disease

“…These electrophilic aldehydes, which are capable of covalent interactions with protein and nucleic acids and have the potential to modify a variety of cellular functions, have been suggested to play a major role in alcoholic liver disease (ALD) progression (2,4,15,41). Previously, we have demonstrated colocalization of 4-HNE and MDA adducts with hepatic microvesicular lipid deposits in female rats receiving a total enteral nutrition diet containing ethanol (EtOH) (34).…”