Cytosolic xanthine oxidoreductase mediated bioactivation of ethanol to acetaldehyde and free radicals in rat breast tissue. Its potential role in alcohol-promoted mammary cancer.
Epidemiological evidence links alcohol intake with increased risk in breast cancer. Not all the characteristics of the correlation can be explained in terms of changes in hormonal factors. In this work, we explore the possibility that alcohol were activated to acetaldehyde and free radicals in situ by xanthine dehydrogenase (XDh) and xanthine oxidase (XO) and/or aldehyde oxidase (AO). Incubation of cytosolic fraction with xanthine oxidoreductase (XDh+XO) (XOR) cosubstrates (e.g. NAD+, hypoxanthine, xanthine, caffeine, theobromine, theophylline or 1,7-dimethylxanthine) significantly enhanced the biotransformation of ethanol to acetaldehyde. The process was inhibited by allopurinol and not by pyrazole or benzoate or desferrioxamine and was not accompanied by detectable formation of 1HEt. However, hydroxylated aromatic derivatives of PBN were detected, suggesting either that hydroxyl free radicals might be formed or that XOR might catalyze aromatic hydroxylation of PBN. No bioactivation of ethanol to acetaldehyde was detectable when a cosubstrate of AO such as N-methylnicotinamide was included in cytosolic incubation mixtures. Results suggest that bioactivation of ethanol in situ to a carcinogen, such as acetaldehyde, and potentially to free radicals, might be involved in alcohol breast cancer induction. This might be the case, particularly also in cases of a high consumption of purine-rich food (e.g. meat) or beverages or soft drinks containing caffeine.
Centro de Investigaciones Toxicológicas (CEITOX)-CITEFA/CONICET, J.B. de La Salle 4397, 1603 Villa Martelli, Buenos Aires, Argentina. ceitox@dd.com.ar
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Castro
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Delgado de Layño
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Costantini
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JA
Castro
D000079:Acetaldehyde / Q000378:metabolism*; D000428:Alcohol Drinking / Q000009:adverse effects; D000818:Animals; D021461:Animals, Outbred Strains; D001711:Biotransformation; D001940:Breast / Q000201:enzymology*; D001943:Breast Neoplasms / Q000139:chemically induced / Q000378:metabolism; D003600:Cytosol / Q000201:enzymology*; D000431:Ethanol / Q000493:pharmacokinetics*; D005260:Female; D005609:Free Radicals / Q000378:metabolism*; D006801:Humans; D051381:Rats; D017207:Rats, Sprague-Dawley; D014968:Xanthine Dehydrogenase / Q000378:metabolism*; D014969:Xanthine Oxidase / Q000378:metabolism*
D005609:Free Radicals; D000431:Ethanol; D014968:Xanthine Dehydrogenase; D014969:Xanthine Oxidase; D000079:Acetaldehyde