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ARS Home » Plains Area » Grand Forks, North Dakota » Grand Forks Human Nutrition Research Center » Dietary Prevention of Obesity-related Disease Research » Research » Publications at this Location » Publication #244798
Title: Ethanol Withdrawal Increases Glutathione Adducts of 4-Hydroxy-2-Hexenal but not 4-Hydroxyl-2-Nonenal in the Rat Cerebral Cortex

Author
item LONG, ERIC - University Of North Dakota
item ROSENBERGER, THAD - University Of North Dakota
item Picklo, Matthew

Submitted to: Free Radical Biology and Medicine
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 10/22/2009
Publication Date: 2/1/2010
Citation: Long, E.K., Rosenberger, T.A., Picklo, M.J. 2010. Ethanol Withdrawal Increases Glutathione Adducts of 4-Hydroxy-2-Hexenal but not 4-Hydroxyl-2-Nonenal in the Rat Cerebral Cortex. Free Radical Biology and Medicine. 48(3):384-390.

Interpretive Summary: Ethanol withdrawal can cause a potentially life-threatening central nervous system response characterized by autonomic hyperactivity and in many cases results in seizures [1-4]. Ethanol withdrawal increases oxidative damage to the polyunsaturated fatty acid (PUFA) docosahexaenoate (DHA; 22:6; n-3) in the CNS. In order to further define the role of oxidative damage of PUFA during ethanol withdrawal, we measured levels of glutathione adducts of 4-hydroxy-2-hexenal (GSHHE) and 4-hydroxy-2-nonenal (GSHNE) as biomarkers of brain lipid peroxidation of n-3 and n-6 PUFA, respectively. In this study rats received an ethanol containing diet for six weeks followed by withdrawal ranging between 0 to 7 days. GSHHE content was elevated (>350%) in the cerebral cortex following 2 days of withdrawal with no change in GSHNE. The levels of GSHHE were significantly greater (2 to 20-fold) than GSHNE in multiple brain regions. Experiments demonstrated that intoxication and withdrawal did not alter the enzymatic rate of formation of GSHHE or GSHNE, but the rate of formation of GSHHE was higher (~50%) than that of GSHNE. These results indicate that selective oxidative damage to n-3 PUFA occurs in the cerebral cortex as a result of ethanol withdrawal and that 4-hydroxy-hexenal is metabolized to the GSH adduct more efficiently than HNE. The extent to which clinical therapy for withdrawal, namely benzodiazepines, inhibit n-3 fatty acid oxidative damage is not known and needs further study.

Technical Abstract: Ethanol withdrawal increases lipid peroxidation of the polyunsaturated fatty acid (PUFA) docosahexaenoate (DHA; 22:6; n-3) in the CNS. In order to further define the role of oxidative damage of PUFA during ethanol withdrawal, we measured levels of glutathione adducts of 4-hydroxy-2-hexenal (GSHHE) and 4-hydroxy-2-nonenal (GSHNE) as biomarkers of brain lipid peroxidation of n-3 and n-6 PUFA, respectively. In this study rats received an ethanol containing diet for six weeks followed by withdrawal ranging between 0 to 7 days. GSHHE content was elevated (>350%) in the cerebral cortex following two days of withdrawal with no change in GSHNE. The levels of GSHHE were significantly greater (2 to 20-fold) than GSHNE in multiple brain regions. Experiments demonstrated that intoxication and withdrawal did not alter the enzymatic rate of formation of GSHHE or GSHNE, but the rate of formation of GSHHE was higher (~50%) than that of GSHNE. These results indicate that selective oxidative damage to n-3 PUFA occurs in the cerebral cortex as a result of ethanol withdrawal and that 4-hydroxy-hexenal is metabolized to the GSH adduct more efficiently than HNE.