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

Drug metabolism letters Pub Date : 2018-01-01 DOI:10.2174/1872312812666180611115418

Emine B Yalcin, Ming Tong, Gina Gallucci, Suzanne M de la Monte

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引用次数: 2

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.

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烟草尼古丁衍生亚硝胺酮(NNK)对脑酒精代谢酶活性的影响

背景:慢性和狂饮酒精暴露的高血液酒精水平在一定程度上通过共同给予烟草特异性尼古丁衍生亚硝胺酮(NNK)而降低，这表明NNK可能改变酒精代谢。目的:我们检测了暴露于乙醇(慢性+暴饮)、NNK或两者的大鼠的乙醇和乙醛代谢酶活性和丙二醛加合物的形成。方法:4周龄Long Evans大鼠分别饲喂含0%或26%乙醇的液体饲料8周。乙醇喂养的大鼠大量灌喂乙醇(2 g/kg;对照组于第7、8周腹腔注射生理盐水(n=12/组)。每组6只大鼠于第3 ~ 8周的周二、周四、周六ig注射NNK (2 mg/kg)或生理盐水。乙醇脱氢酶、过氧化氢酶和醛脱氢酶活性用商业测定法测定。采用定量逆转录-聚合酶链反应检测细胞色素P450 mRNA(17种亚型)水平。采用酶联免疫吸附法测定丙二醛免疫反应性。结果:与对照组(P=0.01)和仅乙醇处理(P=0.04)相比，乙醇和NNK双重暴露显著增加了额叶ADH活性(P=0.01)和ALDH活性(P=0.02)。乙醇+NNK对丙二醛蛋白表达无显著影响。与对照组相比，乙醇降低了CYP1A1 mRNA的表达(P=0.02)，乙醇+NNK联合暴露降低了CYP1A1 (P=0.01)和CYP2C6 (P=0.03)的表达。结论:乙醇和NNK双重暴露可增加脑乙醇代谢，抑制调节外源代谢的cyp450的表达。

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Drug metabolism letters Pharmacology, Toxicology and Pharmaceutics-Pharmaceutical Science

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期刊介绍： Drug Metabolism Letters publishes letters and research articles on major advances in all areas of drug metabolism and disposition. The emphasis is on publishing quality papers very rapidly by taking full advantage of the Internet technology both for the submission and review of manuscripts. The journal covers the following areas: In vitro systems including CYP-450; enzyme induction and inhibition; drug-drug interactions and enzyme kinetics; pharmacokinetics, toxicokinetics, species scaling and extrapolations; P-glycoprotein and transport carriers; target organ toxicity and interindividual variability; drug metabolism and disposition studies; extrahepatic metabolism; phase I and phase II metabolism; recent developments for the identification of drug metabolites.