Chemistry: natural resins or derivatives; peptides or proteins; – Proteins – i.e. – more than 100 amino acid residues – Chemical modification or the reaction product thereof – e.g.,...
Patent
1997-04-08
1999-08-17
Hutzell, Paula K.
Chemistry: natural resins or derivatives; peptides or proteins;
Proteins, i.e., more than 100 amino acid residues
Chemical modification or the reaction product thereof, e.g.,...
530363, 530403, 530405, 530406, 546315, 564502, C07K 100, C07D21170, C07C22100
Patent
active
059395354
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
The chronic consumption of alcoholic beverages is the major cause of serious liver disease. Ethanol is an extremely potent hepatotoxin and can lead to cirrhosis of the liver upon prolonged exposure. In fact 20% of chronic alcoholics will eventually experience cirrhosis. The process of cirrhosis of the liver involves a series of steps beginning with fatty infiltration which leads to necrosis or cell death, then fibrosis which in turn leads to cirrhosis. Despite considerable research in this area, the underlying pathogenic mechanisms of ethanol induced liver injury, including the underlying biochemical reactions, remain obscure.
In recent years extensive evidence has come forward supporting a role of acetaldehyde in the detrimental actions of ethanol in the liver as well as other organs. Numerous studies have shown that acetaldehyde can react with proteins in vitro under physiological conditions to form both stable and unstable adducts. Because of this chemical reactivity, the covalent binding of acetaldehyde to hepatic proteins has been proposed as a key event leading to alcohol liver injury. Many groups have demonstrated by immunoassays, using antibodies directed against acetaldehyde-modified proteins, the presence of acetaldehyde adducts in the livers of rats, guinea pigs, and humans chronically consuming ethanol.
Studies involving the chemistry of acetaldehyde protein adduct formation have shown that acetaldehyde forms both unstable and stable adducts and that the .epsilon.-amino group of lysine participates in binding and, further, that unstable adducts serve as intermediates in stable adduct formation. It has also been found that proteins contain lysine residues with varying reactivities towards acetaldehyde adduct formation and that certain proteins (such as .alpha.-tubulin) may be selective targets for adduct formation by virtue of containing a specially reactive "key" lysine residue. Further information about acetaldehyde adducts is present in Tuma, D. J. "The Role of Acetaldehyde Adducts in Liver Injury", Hall P. Editors, Alcoholic Liver Disease Pathology and Pathogenesis, Ed. 2, London: Edward Arnold, 1995, 89-99 incorporated herein by reference.
The nature and/or chemical structures of acetaldehyde adducts that form in vivo have not been characterized and conflicting results in the literature concerning the nature, subcellular distribution, and identity of these adducts have been reported. See Tuma, D. J. "The Role of Acetaldehyde Adducts in Liver Injury", Hall P. Editors, Alcoholic Liver Disease Pathology and Pathogenesis, Ed. 2, London: Edward Arnold, 1995, 89-99 previously incorporated by reference.
Another reactive aldehyde involved in alcohol liver injury is malondialdehyde (MDA). Malondialdehyde is formed by the peroxidation of polyunsaturated fatty acids and from the oxidative degradation of deoxyribose by a hydroxy radical. MDA is also produced in mammalian tissues as a side product of prostaglandin and thromboxane biosynthesis.
Several studies have suggested that chronic ethanol consumption induces hepatic lipid peroxidation which in turn, generates malondialdehyde. MDA is toxic, mutagenic, and inactivates enzymes due to modification of lysine residues. MDA protein adducts have been detected in the liver following administration of agents that promote lipid peroxidation such as carbon tetrachloride, iron overload, and more recently chronic ethanol feeding. It has been shown to form an adduct with a lysine residue (.epsilon.-amino group) of proteins and that MDA reacts with a primary amine to give a 1:1 Schiff base. For further information about MDA protein adducts see Houglum et al., J. Clin Invest., 86:1991 (1990) incorporated herein by reference.
Similar concentrations of acetaldehyde and MDA can co-exist in the liver during ethanol metabolism, as such both acetaldehyde and MDA adducts have been detected in livers of ethanol fed animals. Ohya demonstrated that malondialdehyde, in the presence of alkanals formed an adduct with the primary amine n-hexylamine.
REFERENCES:
Marco d'Ischia, et al., "Reaction of Malondialdehyde with Amine Neurotransmitters. Formation and Oxidation Chemistry of Fluorescent 1,4-Dihydropyridine Adducts", Tetrahedron, vol. 51, No. 34, pp. 9501-9508 (1995).
Tani et al. "Enhancing Effect of Malondialdehyde Modification on the Mouse IgE Response to Protein Antigens", Agric. Biol. Chem, 1990, vol. 54:9 pp. 2323-2330.
Nair et al. "Novel Fluorescent 1,4-Dihydropyridines", Journ. Am. Chem. Soc., 1986, vol. 108:No. 26 pp. 8283-8285.
Kikugawa et al. "Determination of Malondialdehyde in Oxidized Lipids by the Hantzsch Fluorometric Method", Analytic Biochemistry, 1988, vol. 174, pp. 512-521.
Ohya, Takeshi, "Formation of a New 1,1,1 Adduct in the Reaction of Malondialdehyde, n-Hexylamine and Alkanal under Neutral Conditions", Biol. Pharm. Bull., 1993, vol. 16(2) 137-141.
Bosron, et al., "Genetic Polymorphism of Enzymes of Alcohol Metabolism and Susceptibility to Alcoholic Liver Disease", Molec. Aspects Med., 1988, vol. 10, pp. 147-158.
Groopman, John D., et al., "Molecular Biomarkers for Human Chemical Carcinogen Exposures", Chem. Res. Toxicol., 1993, vol. 6, pp. 764-770.
Kearley et al (Chem. Res. Toxical., 12(1)100-105, 1999.
Tuma et al (Hepatology, 23:872-880), 1996.
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Klassen Lynell W.
McDonald Thomas L.
Sorrell Michael F.
Thiele Geoffrey M.
Tuma Dean J.
Hutzell Paula K.
The Board of Regents of the University of Nebraska
Ungar Susan
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