Journal Article

Ethanol-induced free radicals and hepatic DNA strand breaks are prevented <i>in vivo</i> by antioxidants: effects of acute and chronic ethanol exposure

Panidz Navasumrit, Timothy H. Ward, Nicholas J.F. Dodd and Peter J. O'Connor

in Carcinogenesis

Volume 21, issue 1, pages 93-99
Published in print January 2000 | ISSN: 0143-3334
Published online January 2000 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/21.1.93
Ethanol-induced free radicals and hepatic DNA strand breaks are prevented in vivo by antioxidants: effects of acute and chronic ethanol exposure

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Ethanol was given to male Wistar rats as an acute dose (5 g/kg) or continuously at 5% (w/v) in a liquid diet to provide 36% of the caloric requirement. Free radicals generated in the liver were collected as a stable adduct in bile following the in vivo administration of the spin trapping agent α-(4-pyridyl-1-oxide)-N-tert-butylnitrone (POBN; 700 mg/kg). [1-13C]ethanol was used to confirm the formation of the 1-hydroxyethyl radical and to demonstrate that this was ethanol-derived in the case of the single-dose treatment. Free radical production increased up to 1h after the acute dose and then plateaued over the next 30 min. During chronic exposure to ethanol, free radical generation increased significantly after 1 week and then declined again to remain at a low level over the next 2 weeks; this transient increase corresponded closely with the induction of cytochrome P-450 2E1 (CYP 2E1) in response to ethanol feeding. Single-cell electrophoresis was used to investigate effects on DNA. After an acute dose of ethanol, the frequency of single-strand breaks increased from 1 h to peak at 6 h but then declined again to control values by 12 h. During the chronic exposure, an increase in the frequency of DNA breaks was seen at 3 days, reached a peak at 1 week and then decreased slowly over the next 5 weeks. The effects of antioxidants on these parameters was investigated after an acute dose of ethanol. Pre-treatment with vitamin C (400 mg/kg, i.p., daily for 5 days) or vitamin E (100 mg/kg, i.p., for 5 days) prior to the administration of ethanol (5 g/kg) inhibited generation of the 1-hydroxyethyl–POBN adduct by 30 and 50%, respectively, and both agents prevented the increased frequency of DNA single-strand breaks caused by ethanol. The significance of the temporal coincidence of changes in the above parameters in response to ethanol is discussed.

Keywords: BSA, bovine serum albumin; CYP, cytochrome P450; EGTA, ethylene glycol-bis(2-amino ethyl ether)N,N′-tetraacetic acid; ESR, electron spin resonance; MEOS, microsomal ethanol oxidizing system; POBN, α-(4-pyridyl-1-oxide)-N-tert-butylnitrone; ROS, reactive oxygen species.

Journal Article.  5963 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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