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Stephen S. Hecht - One of the best experts on this subject based on the ideXlab platform.
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Oral Dosing of Dihydromethysticin Ahead of Tobacco Carcinogen NNK Effectively Prevents Lung Tumorigenesis in A/J Mice.
Chemical research in toxicology, 2020Co-Authors: Pedro Corral, Stephen S. Hecht, Pramod Upadhyaya, Sreekanth Narayanapillai, Pablo Leitzman, M. Gerard O'sullivan, Chengguo XingAbstract:Our early studies demonstrated an impressive chemopreventive efficacy of dihydromethysticin (DHM), unique in kava, against tobacco carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced lung tumorigenesis in A/J mice in which DHM was supplemented in the diet. The current work was carried out to validate the efficacy, optimize the dosing schedule, and further elucidate the mechanisms using oral bolus dosing of DHM. The results demonstrated a dose-dependent chemopreventive efficacy of DHM (orally administered 1 h before each of the two NNK intraperitoneal injections, 1 week apart) against NNK-induced lung adenoma formation. Temporally, DHM at 0.8 mg per dose (∼32 mg per kg body weight) exhibited 100% lung adenoma inhibition when given 3 and 8 h before each NNK injection and attained >93% inhibition when dosed at either 1 or 16 h before each NNK injection. The simultaneous treatment (0 h) or 40 h pretreatment (-40 h) decreased lung adenoma burden by 49.8% and 52.1%, respectively. However, post-NNK administration of DHM (1-8 h after each NNK injection) was ineffective against lung tumor formation. In short-term experiments for mechanistic exploration, DHM treatment reduced the formation of NNK-induced O6-methylguanine (O6-mG, a carcinogenic DNA adduct in A/J mice) in the target lung tissue and increased the urinary excretion of NNK detoxification metabolites as judged by the ratio of urinary NNAL-O-gluc to free NNAL, generally in synchrony with the tumor prevention efficacy outcomes in the dose scheduling time-course experiment. Overall, these results suggest DHM as a potential chemopreventive agent against lung tumorigenesis in smokers, with O6-mG and NNAL detoxification as possible surrogate biomarkers.
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Stereospecific deuterium substitution attenuates the tumorigenicity and metabolism of the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK).
Chemical research in toxicology, 2003Co-Authors: John R. Jalas, Edward J. Mcintee, Patrick M.j. Kenney, Pramod Upadhyaya, Lisa A. Peterson, Stephen S. HechtAbstract:Stereochemical determinants of the tumorigenicity and metabolism of the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) were investigated using the stereospecifically deuterated isotopomers (4R)-[4-2H1]NNK and (4S)-[4-2H1]NNK. Upon ip administration to groups of 20 female A/J mice, NNK and (4S)-[4-2H1]NNK exhibited similar lung tumorigenicity at three different doses, whereas (4R)-[4-2H1]NNK was 2-fold less tumorigenic at all three doses. In a parallel experiment, levels of O6-methylguanine and 7-methylguanine were 2-fold lower in lung DNA of mice treated with (4R)-[4-2H1]NNK than in mice treated with NNK or (4S)-[4-2H1]NNK. To corroborate these in vivo data, the in vitro metabolism of these compounds was investigated using A/J mouse lung microsomes and Spodoptera frugiperda (Sf9)-expressed mouse cytochrome P450s 2A4 and 2A5. Kinetic isotope effects on the apparent Vmax (DV) for the product of NNK 4-hydroxylation, OPB, were 2.7 ± 0.2 and 2.8 ± 0.4 when (4R)- and (4S)-[4-2...
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Recent Studies on Mechanisms of Bioactivation and Detoxification of 4-(Methylnitrosamino)-1-(3-Pyridyl)-1-Butanone (NNK), A Tobacco-Specific Lung Carcinogen
Critical reviews in toxicology, 1996Co-Authors: Stephen S. HechtAbstract:This article reviews recent advances in the biochemistry and molecular biology of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), a tobacco-specific pulmonary carcinogen believed to be involved in the induction of lung cancer in smokers. Several aspects of NNK bioactivation are addressed, including identification of its metabolites in laboratory animals and humans, cytochrome P450 enzyme involvement in its metabolic activation, DNA and protein adduct formation, biological significance of the major DNA adducts formed, and mutations in oncogenes from tumors induced by NNK. Collectively, the presently available data provide a reasonably clear picture of NNK bioactivation in rodents, although there are still important gaps in our mechanistic understanding of NNK-induced tumorigenesis. The studies in rodents and primates have facilitated development of methods to assess NNK bioactivation in humans, which will be applicable to studies of lung cancer susceptibility and prevention.
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Inhibition of tobacco-specific nitrosamine 4-(N-nitrosomethylamino)-1-(3-pyridyl)-1-butanone (NNK) tumorigenesis with aromatic isothiocyanates.
IARC scientific publications, 1991Co-Authors: Mark A. Morse, Stephen S. Hecht, Karin I. Eklind, Fung-lung ChungAbstract:4-(N-Nitrosomethylamino)-1-(3-pyridyl)-1-butanone (NNK) is a potent tobacco-specific carcinogenic nitrosamine. At low doses, it induces primarily lung tumours in mice, hamsters and rats, regardless of the route of administration. Its unique organ specificity and potency suggest its possible role in the high incidence of lung cancer in smokers. The goal of this study was to find agents that would potentially prevent NNK tumorigenesis. Previous results led us to test phenethyl isothiocyanate (PEITC) on NNK tumorigenesis in a two-year bioassay in Fischer 344 rats. The NNK-treated group developed 80% lung tumour incidence, whereas NNK-treated rats fed PEITC diets had only 40% lung tumour incidence. Incidences in other organs were not affected by this treatment. We also tested PEITC in a 16-week, short-term bioassay against NNK-induced lung adenomas in A/J mice. Pretreatment of mice with PEITC by gavage at four daily doses of 5 mumol or 25 mumol reduced the formation of NNK-induced lung adenomas by 70% or 100%, respectively. Interestingly, benzyl isothiocyanate and phenyl isothiocyanate, the lower homologues of PEITC, were inactive in this bioassay. Using a protocol similar to that used in the bioassays, PEITC was shown to decrease DNA methylation by NNK in the lungs of rats and mice and suppress the metabolism of NNK by mouse lung microsomes. These results are consistent with the previous data, suggesting that the inhibition of NNK-induced lung tumour formation by PEITC is a consequence of reduced DNA methylation caused by inhibition of NNK metabolism.(ABSTRACT TRUNCATED AT 250 WORDS)
George G. Chen - One of the best experts on this subject based on the ideXlab platform.
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tumorigenesis of smoking carcinogen 4 methylnitrosamino 1 3 pyridyl 1 butanone is related to its ability to stimulate thromboxane synthase and enhance stemness of non small cell lung cancer stem cells
Cancer Letters, 2016Co-Authors: Shucai Yang, Malcolm J. Underwood, Mingyue Li, Runyue Huang, Calvin S H Ng, Xiang Long, Jun Wu, Bin Wu, Jing Du, George G. ChenAbstract:Lung cancer stem cells (LCSCs) play a critical role in lung cancer development, however, it is unknown whether thromboxane synthase (TXS) plays a role in the maintenance of LCSCs stemness. This study aimed to determine the in vivo role of TXS in lung cancer induced by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), a smoking carcinogen. Results showed that ozagrel, a TXS blocker, suppressed NNK-induced lung tumors in mice. The expressions of CD133 and ALDH1A1 were positively associated with TXS. Similar results were observed in human NSCLC tumor samples. NNK significantly stimulated TXS and enhanced the generation of LCSCs, evident by the upregulation of CD133 and ALDH1A1 expression, and the increase in the number and size of tumor spheres. NNK also promoted the expression of LCSC-related molecules including β-catenin and Nanog. All these NNK-mediated effects could be offset by ozagrel. In the colony formation assay, NNK increased whereas ozagrel decreased the number of colonies. Collectively, LCSCs and TXS participate in NNK-induced lung cancer. Our data suggest that TXS is a promising therapeutic target as it is a key molecular in NNK-mediated stemness of LCSCs.
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Abstract 4013: The positive role of TPγ in the induction of COX-2, TxA2 and cell growth by NNK in human lung cancer cells
Molecular and Cellular Biology, 2012Co-Authors: Runyue Huang, George G. Chen, Paul B.s. LaiAbstract:Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL Many studies have shown that 4-Methylnitrosamino-1-3-pyridyl-1-butanone (NNK), the most potent carcinogen present in tobacco smoke, can induce lung tumor growth. We previously demonstrated that the activation of extracellular regulated protein kinases (ERK) and cAMP response element-binding protein (CREB) is responsible for the pro-survival and proliferative effects of thromboxane A2 (TxA2) and its receptor (TP) in the human lung cancer cells stimulated with NNK (reported in oncogene journal). In current study, we further determined the role of cyclooxygenase(COX)-2/TxA2/TP pathway in lung cancer cell growth mediated by NNK. TP exists as two isoforms, ≤ and β, in human beings. Western blotting showed that TPα, but not TPα, was widely expressed in a series of human lung cells. NCI-H23 and CRL-2066, which express both TPγ and TPα, were selected as models in this study. COX-2 inhibitor NS398 could significantly reduce NNK-stimulated TxA2 synthesis. Moreover, NS398 and BM567, an agent combining TxA2 synthase inhibition and TP antagonism, had the similar effects to reverse NNK-induced activation of ERK and CREB and the increase in cell growth. Furthermore, the administration of TxA2 mimetic U46619 could almost reconstituted NNK-induced ERK and CREB activation in the presence of COX-2-siRNA. Collectively, these findings suggest that in lung cancer cells stimulated with NNK, TxA2 is mainly derived from COX-2 and acts as a key mediator for tumor-promoting effects of COX-2. Interestingly, TP antagonist SQ29548 could inhibit NNK-induced COX-2 protein expression and TxA2 production, indicating that TP is able to modulate NNK-induced COX-2 expression and activity, thereby constituting an auto-amplification mechanism of TxA2 synthesis in lung cancer cells stimulated with NNK. We further examined which TP isoform contributes to the NNK effects. We observed that the protein expression of TPα, but not TPα, was time-dependently increased by NNK. Moreover, the activation of ERK and CREB and the production of COX-2 and TxA2 by NNK were potentiated in cells transfected with pcDNA3-TPγ as compared with cells transfected with control vector or pcDNA3-TPα, and such effects could be reversed by SQ29548. However, in cells transfected with pcDNA3-TPα, the COX-2, TxA2, phospho-ERK and phospho-CREB levels were similar to that seen in the cells transfected with control vector, and neither NNK nor SQ29548 had any additional effects when compared to the control cells. Taken together, these data strongly suggest that TPγ rather than TPγ is, at least in part, responsible for the induction of COX-2, TxA2 and cell growth by NNK in lung cancer cells. Our study implies that targeting TxA2 and its receptor TPγ may represent a promising strategy for prevention of smoking-associated lung cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4013. doi:1538-7445.AM2012-4013
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4 methylnitrosamino 1 3 pyridyl 1 butanone NNK promotes lung cancer cell survival by stimulating thromboxane a 2 and its receptor
Oncogene, 2011Co-Authors: R Y Huang, Michael K.y. Hsin, Tony Mok, Malcolm J. Underwood, L T, Timothy D Warner, George G. ChenAbstract:The role of thromboxane A(2) (TxA(2)) in smoking-associated lung cancer is poorly understood. This study was conducted to study the role of TxA(2) in smoking carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-promoted cell survival and growth in human lung cancer cells. We found that NNK increased TxA(2) synthase (TxAS) expression and thromboxane B(2) (TxB(2)) generation in cultured lung cancer cells, the result of which was supported by the increased level of TxAS in lung cancer tissues of smokers. Both TxAS-specific inhibitor furegrelate and TxA(2) receptor antagonist SQ29548 completely blocked NNK-mediated cell survival and growth via inducting apoptosis. TxA(2) receptor agonist U46619 reconstituted a near-full survival and growth response to NNK when TxAS was inhibited, affirming the role of TxA(2) receptor in NNK-mediated cell survival and growth. Suppression of cyclic adenosine monophosphate response element binding protein (CREB) activity by its small interference RNA blocked the effect of NNK. Phosphatidylinositol 3-kinase (PI3K)/Akt and extracellular signal-regulated kinase (ERK) also had a positive role. Altogether, our results have revealed that NNK stimulates TxA(2) synthesis and activates its receptor in lung cancer cells. The increased TxA(2) may then activate CREB through PI3K/Akt and extracellular ERK pathways, thereby contributing to the NNK-promoted survival and growth of lung cancer cells.
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PPARγ activation extinguishes smoking carcinogen by inhibiting NNK-mediated proliferation
American journal of respiratory cell and molecular biology, 2009Co-Authors: Michael K.y. Hsin, Johnson H.y. Yip, Tony Mok, Malcolm J. Underwood, George G. ChenAbstract:Among the carcinogenic chemicals of cigarette smoking, 4-(methylnitrosamino-1-(3-pyridyl)-1-butanone (NNK) is the most potent. The activation of peroxisome proliferator-activated receptor (PPAR)γ can arrest the growth of lung cancer. We hypothesized that PPARγ activation inhibits NNK-mediated proliferation of lung cancer cells. PPARγ expression was increased in 94.7% human lung cancer tumor tissues, compared with their paired corresponding nontumor tissues. PPARγ was also found to be abundant in all the lung cancer cell lines tested. Troglitazone dose-dependently inhibited the NNK-mediated proliferation of lung cancer cells that expressed PPARγ. Troglitazone blocked NNK-induced up-regulation of HO-1, Bcl-2, and c-IAP2, and recovered Bad activity that was suppressed by NNK. NNK promoted the nuclear p21, whereas troglitazone increased cytosolic p21. Troglitazone increased PPARγ transcriptional activity in NNK-treated cells and a PPARγ dominant-negative inhibitor completely suppressed the action of troglitaz...
Robert W. Teel - One of the best experts on this subject based on the ideXlab platform.
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Modulation of the mutagenicity and metabolism of the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) by phenolic compounds
Mutation research, 1996Co-Authors: Cecil Miller, Andre Castonguay, Robert W. TeelAbstract:Abstract NNK is a potent environmental carcinogen generated during tobacco processing and smoking. The carcinogenic response to tobacco smoking is modulated by nutritional factors. In this study, liver microsomes from phenobarbital and β-naphthoflavone-treated or control hamsters were used to assay the mutagenicity ( Salmonella typhimurium TA1535) of NNK. Western analysis of these microsomal preparations revealed an increased expression of protein recognized by polyclonal antibodies specific for P-450 1A2 in β-naphthoflavone-induced microsomes and P-450 2B1/2B2 in phenobarbital-induced microsomes. Both inducers significantly increased the mutagenicity of NNK. Metabolism of NNK by the three microsomal preparations was compared. Metabolites formed by methyl-hydroxylation of NNK by microsomes from control animals were significantly greater than those formed by α-methylene hydroxylation. Phenobarbital treatment had the greatest effect on α-methylene hydroxylation while β-naphthoflavone had the greatest effect on methyl hydroxylation. The antimutagenic action of the polyphenolic compounds ellagic acid, esculetin and propyl gallate correlated with an inhibition of the metabolism of NNK. There were, however, differences in the effects of these compounds on specific pathways of NNK metabolism depending upon the microsomal enzyme induction treatment. This suggests that phenolic compounds have selective affinity for specific P-450 isozymes activating NNK.
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Effects of compounds of plant origin on the mutagenicity and metabolism of the tobacco-specific nitrosamine NNK
Phytotherapy Research, 1994Co-Authors: C. H. Miller, S. M. Hamilton, Robert W. TeelAbstract:We have investigated the effects of five phytochemicals on the microsomal-dependent mutagenicity and metabolism of the tobacco-specific nitrosamine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). Two compounds, d-limonene and silymarin, had no effect on NNK-induced mutagenesis in Salmonella typhimurium TA1535 over the concentration range of 0.1–0.4 μmol/plate. Diallyl sulphide was weakly antimutagenic at a concentration of 0.4 μmol/plate. Both capsaicin and tannic acid showed a dose-dependent inhibition of mutagenesis in TA1535. Metabolism studies using [3H]NNK indicated that the effects of the phytochemicals on NNK-induced mutagenesis did not always correlate with the effects on NNK metabolism. α-Carbon hydroxylation reactions are considered the most significant pathways involved in the metabolic activation of NNK to mutagenic and carcinogenic species. D-Limonene and silymarin (0,4 μmol) had the least inhibitory effect on the total α-carbon hydroxylation reactions, 19% and 28%. Capsaicin and diallyl sulphide inhibited these pathways by 74% and 70%. Tannic acid, the most potent phytochemical tested in this study, inhibited total α-carbon hydroxylation pathways by 99%.
Ming Tong - One of the best experts on this subject based on the ideXlab platform.
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Effects of Tobacco Nicotine-Derived Nitrosamine Ketone (NNK) Exposures on Brain Alcohol Metabolizing Enzyme Activities.
Drug metabolism letters, 2018Co-Authors: Emine B Yalcin, Ming Tong, Gina Gallucci, Suzanne M De La MonteAbstract: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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differential contributions of alcohol and the nicotine derived nitrosamine ketone NNK to insulin and insulin like growth factor resistance in the adolescent rat brain
Alcohol and Alcoholism, 2015Co-Authors: Ming Tong, Chetram Deochand, Suzanne M De La MonteAbstract:Aims Since epidemiologic studies suggest that tobacco smoke toxins, e.g. the nicotine-derived nitrosamine ketone (NNK) tobacco-specific nitrosamine, can be a co-factor in alcohol-related brain disease (ARBD), we examined the independent and additive effects of alcohol and NNK exposures on spatial learning/memory, and brain insulin/IGF signaling, neuronal function and oxidative stress. Methods Adolescent Long Evans rats were fed liquid diets containing 0 or 26% caloric ethanol for 8 weeks. During weeks 3–8, rats were treated with i.p. NNK (2 mg/kg, 3×/week) or saline. In weeks 7–8, ethanol groups were binge-administered ethanol (2 g/kg; 3×/week). In week 8, at 12 weeks of age, rats were subjected to Morris Water Maze tests. Temporal lobes were used to assess molecular indices of insulin/IGF resistance, oxidative stress and neuronal function. Results Ethanol and NNK impaired spatial learning, and NNK ± ethanol impaired memory. Linear trend analysis demonstrated worsening performance from control to ethanol, to NNK, and then ethanol + NNK. Ethanol ± NNK, caused brain atrophy, inhibited insulin signaling through the insulin receptor and Akt, activated GSK-3β, increased protein carbonyl and 3-nitrotyrosine, and reduced acetylcholinesterase. NNK increased NTyr. Ethanol + NNK had synergistic stimulatory effects on 8-iso-PGF-2α, inhibitory effects on p-p70S6K, tau and p-tau and trend effects on insulin-like growth factor type 1 (IGF-1) receptor expression and phosphorylation. Conclusions Ethanol, NNK and combined ethanol + NNK exposures that begin in adolescence impair spatial learning and memory in young adults. The ethanol and/or NNK exposures differentially impair insulin/IGF signaling through neuronal growth, survival and plasticity pathways, increase cellular injury and oxidative stress and reduce expression of critical proteins needed for neuronal function.
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potential contributions of the tobacco nicotine derived nitrosamine ketone NNK in the pathogenesis of steatohepatitis in a chronic plus binge rat model of alcoholic liver disease
Alcohol and Alcoholism, 2015Co-Authors: Ming Tong, Valerie Zabala, Teresa Ramirez, Emine B Yalcin, Silvia Balbo, Elizabeth Silbermann, Chetram DeochandAbstract:Aims: Alcoholic liver disease (ALD) is linked to binge drinking and cigarette smoking. Heavy chronic ± binge alcohol, or low-level exposures to dietary nitrosamines cause steatohepatitis with insulin resistance and oxidative stress in animal models. This study examines hepatotoxic effects of sub-mutagenic exposures to tobacco-specific nitrosamine (NNK) in relation to ALD. Methods: Long Evans rats were fed liquid diets containing 0 or 26% (caloric) ethanol (EtOH) for 8 weeks. In Weeks 3 through 8, rats were treated with NNK (2 mg/kg) or saline by i.p. injection, 3×/week, and in Weeks 7 and 8, EtOH-fed rats were binge-administered 2 g/kg EtOH 3×/week; controls were given saline. Results: EtOH ± NNK caused steatohepatitis with necrosis, disruption of the hepatic cord architecture, ballooning degeneration, early fibrosis, mitochondrial cytopathy and ER disruption. Severity of lesions was highest in the EtOH+NNK group. EtOH and NNK inhibited insulin/IGF signaling through Akt and activated pro-inflammatory cytokines, while EtOH promoted lipid peroxidation, and NNK increased apoptosis. O6 -methyl-Guanine adducts were only detected in NNK-exposed livers. Conclusion: Both alcohol and NNK exposures contribute to ALD pathogenesis, including insulin/IGF resistance and inflammation. The differential effects of EtOH and NNK on adduct formation are critical to ALD progression among alcoholics who smoke.
Suzanne M De La Monte - One of the best experts on this subject based on the ideXlab platform.
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Effects of Tobacco Nicotine-Derived Nitrosamine Ketone (NNK) Exposures on Brain Alcohol Metabolizing Enzyme Activities.
Drug metabolism letters, 2018Co-Authors: Emine B Yalcin, Ming Tong, Gina Gallucci, Suzanne M De La MonteAbstract: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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differential contributions of alcohol and the nicotine derived nitrosamine ketone NNK to insulin and insulin like growth factor resistance in the adolescent rat brain
Alcohol and Alcoholism, 2015Co-Authors: Ming Tong, Chetram Deochand, Suzanne M De La MonteAbstract:Aims Since epidemiologic studies suggest that tobacco smoke toxins, e.g. the nicotine-derived nitrosamine ketone (NNK) tobacco-specific nitrosamine, can be a co-factor in alcohol-related brain disease (ARBD), we examined the independent and additive effects of alcohol and NNK exposures on spatial learning/memory, and brain insulin/IGF signaling, neuronal function and oxidative stress. Methods Adolescent Long Evans rats were fed liquid diets containing 0 or 26% caloric ethanol for 8 weeks. During weeks 3–8, rats were treated with i.p. NNK (2 mg/kg, 3×/week) or saline. In weeks 7–8, ethanol groups were binge-administered ethanol (2 g/kg; 3×/week). In week 8, at 12 weeks of age, rats were subjected to Morris Water Maze tests. Temporal lobes were used to assess molecular indices of insulin/IGF resistance, oxidative stress and neuronal function. Results Ethanol and NNK impaired spatial learning, and NNK ± ethanol impaired memory. Linear trend analysis demonstrated worsening performance from control to ethanol, to NNK, and then ethanol + NNK. Ethanol ± NNK, caused brain atrophy, inhibited insulin signaling through the insulin receptor and Akt, activated GSK-3β, increased protein carbonyl and 3-nitrotyrosine, and reduced acetylcholinesterase. NNK increased NTyr. Ethanol + NNK had synergistic stimulatory effects on 8-iso-PGF-2α, inhibitory effects on p-p70S6K, tau and p-tau and trend effects on insulin-like growth factor type 1 (IGF-1) receptor expression and phosphorylation. Conclusions Ethanol, NNK and combined ethanol + NNK exposures that begin in adolescence impair spatial learning and memory in young adults. The ethanol and/or NNK exposures differentially impair insulin/IGF signaling through neuronal growth, survival and plasticity pathways, increase cellular injury and oxidative stress and reduce expression of critical proteins needed for neuronal function.