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Effects of Tobacco Nicotine-Derived Nitrosamine Ketone (NNK) Exposures on Brain Alcohol Metabolizing Enzyme Activities

[ Vol. 12 , Issue. 2 ]

Author(s):

Emine B. Yalcin, Ming Tong, Gina Gallucci and Suzanne M. de la Monte*   Pages 117 - 124 ( 8 )

Abstract:


Background: The high levels of blood alcohol achieved with chronic plus binge alcohol exposures are somewhat reduced by co-administration of tobacco-specific Nicotine-Derived Nitrosamine Ketone (NNK) suggesting that NNK may alter alcohol metabolism.

Objective: We examined ethanol and acetaldehyde-metabolizing enzyme activities and malondialdehyde adduct formation in rats exposed to ethanol (chronic + binge), NNK, or both.

Methods: 4-week old Long Evans rats were fed liquid diets containing 0% or 26% caloric ethanol for 8 weeks. Ethanol-fed rats were binge-administered ethanol (2 g/kg; on Mondays, Wednesdays, and Fridays) by intraperitoneal (i.p.) injection, while control group administered saline in weeks 7 and 8 (n=12/group). Six rats from each group were administered i.p. injections of NNK (2 mg/kg) or saline on Tuesdays, Thursdays, and Saturdays of weeks 3 through 8. Alcohol dehydrogenase, catalase, and aldehyde dehydrogenase activities were measured using commercial assays. Cytochrome P450 mRNA levels (17 isoforms) were measured by quantitative reverse transcription-polymerase chain reaction. Malondialdehyde immunoreactivity was measured by enzyme-linked immunosorbent assay.

Results: Dual exposures to ethanol and NNK significantly increased frontal lobe ADH activity relative to control (P=0.01) and ethanol only (P=0.04) treatments, and ALDH relative to control (P=0.02). In contrast, malondialdehyde-protein expression was not significantly altered by ethanol+NNK. Ethanol decreased CYP1A1 mRNA expression relative to control (P=0.02), and combined ethanol+NNK exposures decreased the expression of CYP1A1 (P=0.01) and CYP2C6 (P=0.03).

Conclusion: Dual exposures to ethanol and NNK increase brain ethanol metabolism and inhibit the expression of CYP450s that regulate xenobiotic metabolism.

Keywords:

Ethanol metabolism, alcohol dehydrogenase, aldehyde dehydrogenase, catalase, cytochrome p450, malondialdehyde.

Affiliation:

Liver Research Center, Division of Gastroenterology and Department of Medicine, Rhode Island Hospital and The Alpert Medical School of Brown University, Providence, RI, Liver Research Center, Division of Gastroenterology and Department of Medicine, Rhode Island Hospital and The Alpert Medical School of Brown University, Providence, RI, Liver Research Center, Division of Gastroenterology and Department of Medicine, Rhode Island Hospital and The Alpert Medical School of Brown University, Providence, RI, Liver Research Center, Division of Gastroenterology and Department of Medicine, Rhode Island Hospital and The Alpert Medical School of Brown University, Providence, RI

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