Effects of Tobacco Nicotine-Derived Nitrosamine Ketone (NNK) Exposures on Brain Alcohol Metabolizing Enzyme Activities.
Effects of Tobacco Nicotine-Derived Nitrosamine Ketone (NNK) Exposures on Brain Alcohol Metabolizing Enzyme Activities.
复制标题
DOI：
10.2174/1872312812666180611115418
复制
发表时间：
2018
影响因子：
--
通讯作者：
中科院分区：
文献类型：
--
作者：
通过联合给予烟草特异性尼古丁衍生的亚硝胺酮（NNK），慢性加酗酒暴露所达到的高水平血液酒精在一定程度上降低，表明NNK可能改变酒精代谢。我们研究了暴露于乙醇（慢性+暴饮暴食）、NNK或两者的大鼠中乙醇和乙酰丙酮酸去代谢酶的活性和丙二醛加合物的形成。4-用含0%或26%热量乙醇的流质饲料喂养10周龄Long Evans大鼠8周。通过腹膜内（i. p.）对照组在第7周和第8周注射生理盐水（n=12/组）。在第3周至第8周的星期二、星期四和星期六，对每组6只大鼠腹膜内注射NNK（2 mg/kg）或生理盐水。醇脱氢酶，过氧化氢酶，和醛脱氢酶活性测定使用商业测定。定量逆转录聚合酶链反应测定细胞色素P450 mRNA水平（17种亚型）。酶联免疫吸附试验测定丙二醛免疫反应性。与对照组（P=0.01）和仅乙醇组（P=0.04）相比，乙醇和NNK双重暴露显著增加额叶ADH活性，与对照组相比，ALDH活性显著增加（P=0.02）。相比之下，乙醇+NNK没有显著改变丙二醛蛋白表达。与对照组相比，乙醇降低了CYP 1A 1 mRNA表达（P=0.02），乙醇+NNK联合暴露降低了CYP 1A 1（P=0.01）和CYP 2C 6（P=0.03）的表达。乙醇和NNK的双重暴露增加脑乙醇代谢并抑制调节异生物质代谢的CYP 450的表达。
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. We examined ethanol and acetaldehyde-metabolizing enzyme activities and malondialdehyde adduct formation in rats exposed to ethanol (chronic + binge), NNK, or both. 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 3 weeks 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. 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). Dual exposures to ethanol and NNK increase brain ethanol metabolism and inhibit the expression of CYP450s that regulate xenobiotic metabolism.