Hydroxy nonenal

Dick et al. [88] studied the antioxidant effects of NADPH-dependent alkenal/one oxidor-eductase (AO), also known as leukotriene B4 12-hydroxydehydrogenase, 15-oxoprostaglan-din 13-reductase, and dithiolethione-inducible gene-1. It was found that AO catalyzed the hydrogenation of many a,(3-unsaturated aldehydes and ketones and protected against cytotoxic action of 4-hydroxy-2-nonenal. 

The importance of superoxide-mediated damage to cancer cells was also demonstrated in the experiments with overexpressed mitochondrial MnSOD. Hirose et al. [186] showed that the overexpression of mitochondrial MnSOD enhanced the survival of human melanoma cells exposed to cytokines IL-1 and TNF-a, anticancer antibiotics doxorubicin and mitomycin C, and y-irradiation. Similarly, Motoori et al. [187] found that overexpression of MnSOD reduced the levels of reactive oxygen species in mitochondria, the intracellular production of 4-hydroxy-2-nonenal, and prevented radiation-induced cell death in human hepatocellular... 

Liu, Y., Xu, G., and Sayre, L. M. (2003). Carnosine inhibits (E)-4-hydroxy-2-nonenal-induced protein cross-linking Structural characterization of the carnosine-HNE adducts. Chem. Res. Toxicol. 16,1589-1597. 

An intermediate in Eq. 21-13 may be converted to 4-hydroxy-2-nonenal, a prominent product of the peroxidation of arachidonic or linoleic acids (Eq. 21-15).242 243a However, other biosynthetic pathways to this compound are possible.244 2443 4-Hydroxy-2-nonenal can react with side chains of lysine, cysteine, and histidine245 to form fluorescent products such as the following cyclic compound generated by an oxidative reaction.246... 

Friguet B., Stadtman E. R., and Szweda L. I. (1994). Modification of glucose-6-phosphate dehydrogenase by 4-hydroxy-2-nonenal. J. Biol. Chem. 269 21639-21643. 

Perluigi M., Poon H. F., Hensley K., Pierce W. M., Klein J. B., Calabrese V., De Marco C., and Butterfield D. A. (2005). Proteomic analysis of 4-hydroxy-2-nonenal-modified proteins in G93A-SOD1 transgenic mice - A model of familial amyotrophic lateral sclerosis. Free Radical Biol. Med. 38 960-968. 

The pathological characteristic of Parkinson s disease is the selective degeneration of dopamine neurons in the pars compacta of the substantia nigra. The mechanism for the loss of neurons remains to be elucidated, and recently apoptosis has been proposed as a death process in Parkinson s disease. For example, the level of a product of the oxidative stress, 4-hydroxy-2-nonenal protein adduct, was found to increase in the nigral neurons of parkinsonian brains. Peroxynitrite (see Figure 13.6) has been proposed to be involved in the neuronal cell death in some neurodegenerative diseases, such as amyotrophic lateral sclerosis. 

The aldehydic products from the autoxidation of PUFA have always been of interest, since the thiobarbituric acid (TBA) test detects malonaldehyde (or malonaldehyde precursors) with considerable sensitivity (76-78) and since malonaldehyde itself is mutagenic (H). More recently, Esterbauer and his coworkers have shown that 4-hydroxy-2-alkenals, and particularly 4-hydroxy-2-nonenal, are extremely cytotoxic (76f77,7Q). 

The insensitivity of this reaction towards oxygen makes it very attractive for media where the exclusion of air is not possible, for example, in vivo. As an example, the biologically relevant 4-hydroxy-2-nonenal was released photochemically from an anthraquinone precursor. Interestingly, the phototrigger is reoxidized by molecular oxygen during the reaction (Scheme 13.15) [60]. 

Brinson, R.G. and Jones, P.B. (2004) Caged trans-4-hydroxy-2-nonenal. 

Figure 13.7. Glutathione conjugation to reactive metabolites by GSTs. Ultimate carcinogens such as benzo[a]pyrene 7,8-diol 9,10-epoxide and aflatoxin B1 8,9-epoxide are glutathione-conjugated for detoxification by GSTM1, GSTp, and GST A, respectively. Lipid peroxidation product 4-hydroxy-2-nonenal is preferentially detoxified by GSTA.

Figure 22.7. The major DNA lesions of the lipid peroxidation products. (A) DNA lesions produced by malondialdehyde. Mi denotes the monomeric form of malondialdehyde. Malo-ndialdehyde can polymerize to form dimers and trimers that can also react with DNA. The resulting lesions are designated as M2 and M3, respectively (c.g., M2G). These lesions, however, may not be significant in cells as polymerization of malondialdehyde is relatively slow at neutral pH. (B) The l,7V2-propano-dG DNA adducts produced by acrolein, crotonaldehyde, and 4-hydroxy-2-nonenal (HNE). Stereochemistry is not shown. The l.A -acrolcin-dG consists of three isomers. The 1, AAcrotonaldchyde-dG consists of two isomers. The FAAlINF-dGconsistsof four isomers. (C)EthenoDNAadductsproduced by 2,3-epoxy-4-hydroxynonenal. Further oxidation of 4-hydroxynonenal produces 2,3-epoxy-4-hydroxynonenal, which reacts with DNA to form the exocyclic etheno adducts.

Butterfield DA, Reed T, Perluigi M, De Marco C, Cocda R, Cini C, Sultana R (2006b) Elevated protein-bound levels of the lipid peroxidation product, 4-hydroxy-2-nonenal, in brain from persons with mUd cognitive impairment. Neurosci Lett 397 170-173 Butterfield DA, Stadtman ER (1997) Protein oxidation processes in aging brain. Adv CeU Aging Gerontol vol. 2 pp. 161-191... 

Hamdane M, Delobel P, Sambo AV, Smet C, Begard S, fioUeau A, Landrieu I, Delacourte A, Lippens G, Flament S, Buee L (2003) Neurofibrillary degeneration of the Alzheimer-type tm alternate pathway to neuronal apoptosis Biochem Pharmacol 66 1619-1625 Hayashi T, Shishido N, Nakayama K, Nunomura A, Smith MA, Perry G, Nakamura M (2007) Lipid peroxidation and 4-hydroxy-2-nonenal formation by copper ion bound to amyloid-beta peptide. Free Radic Biol Med 43 1552-1559... 

Another important example of the Michael addition in biochemistry and molecnlar biology is the reaction of 4-hydroxynon-2-enal with amines and snlfydryl gronps (Winter, C.K., Segall, H.J., and Haddon, W.F., Formation of cyclic addncts of deoxygnanosine with the aldehyde trans-4-hydroxy-2-hexenal and fran.y-4-hydroxy-2-nonenal in vitro. Cancer Res. 46, 5682-5686, 1986 Sayre, L.M., Arora, P.K., Iyer, R.S., and Salomon, R.G., Pyrrole formation from 4-hydroxynonenal and primary amines, Chem. Res. Toxicol. 6, 19-22, 1993 Hartley, D.P, Ruth, J.A., and Petersen,... 

Eenaille E, Guy PA. Study of protein modification by 4-hydroxy-2-nonenal and other short chain aldehydes analyzed by electrospray ionization tandem mass spectrometry. J. Am. Soc. Mass Spectrom. 2003 14 215-226. 

Minekura H, Kumagai T, Kawamoto Y, Nara F and Uchida K, 4-Hydroxy-2-nonenal is a powerful endogenous inhibitor of endothelial response. Biochem Biophys Res Commun 282(2) 557-61, 2001. 

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