Free radicals as mediators of alcohol toxicity.
In this article we have reviewed recent evidence in support of the hypothesis that acute/chronic alcohol toxicity is mediated primarily via the generation of damaging free radical species in various tissues. Studies in man, animal model or in vitro experimental systems have shown: (1) the demonstration of alcohol-induced free radical species directly via esr spectroscopic analysis; (2) increases in indirect markers of ethanol-induced free radical damage in tissues, such as lipid peroxides and protein carbonyl; (3) ethanol-induced alterations in the levels of endogenous tissue antioxidants. These data show the induction of free radicals by ethanol to be a complex interactive process. The classical pathway for ethanol metabolism, catalysed by alcohol dehydrogenase to form acetaldehyde, results in the formation of free radicals, resulting from concomitant changes in NADH levels and NADH/NAD+ redox ratios, which in turn modulate the activity of the free radical generating enzyme xanthine oxidase. The induction of CYP 2E1 in the microsomes results in the generation of HER, another major route by which ethanol induces free radical formation. In addition to the above, ethanol may also induce free radical formation via the reaction of aldehyde oxidase with acetaldehyde or NADH to generate oxyradicals via disturbance in the metabolism of the pro-oxidant iron, or via increased efflux from mitochondria following altered mitochondrial oxidative metabolism.
Mantle
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Department of Neurochemistry, Newcastle General Hospital, Newcastle upon Tyne, UK.
Preedy
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D000437:Alcoholism / Q000628:therapy*; D000975:Antioxidants / Q000378:metabolism*; D015415:Biomarkers / Q000032:analysis; D002986:Clinical Trials as Topic; D000431:Ethanol / Q000494:pharmacology / Q000633:toxicity*; D005609:Free Radicals / Q000494:pharmacology*; D006801:Humans; D009569:Nitric Oxide / Q000096:biosynthesis; D018384:Oxidative Stress / Q000187:drug effects*; D013057:Spectrum Analysis
D000975:Antioxidants; D015415:Biomarkers; D005609:Free Radicals; D009569:Nitric Oxide; D000431:Ethanol