The Experts below are selected from a list of 228 Experts worldwide ranked by ideXlab platform
Chengguo Xing - One of the best experts on this subject based on the ideXlab platform.
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A stable isotope dilution tandem mass spectrometry method of major kavalactones and its applications
PLOS ONE, 2018Co-Authors: Yi Wang, Shainnel O. Eans, Heather M. Stacy, Sreekanth Narayanapillai, Abhisheak Sharma, Naomi Fujioka, Linda G. Haddad, Jay P. Mclaughlin, Bonnie A. Avery, Chengguo XingAbstract:Kava is regaining its popularity with detailed characterizations warranted. We developed an ultraperformance liquid chromatography high-resolution tandem mass spectrometry (UPLC-MS/MS) method for major kavalactones (kavain, dihydrokavain, methysticin, Dihydromethysticin and desmethoxyyangonin) with excellent selectivity and specificity. The method has been validated for different matrices following the Food and Drug Administration guidance of analytical procedures and methods validation. The scope of this method has been demonstrated by quantifying these kavalactones in two kava products, characterizing their tissue distribution and pharmacokinetics in mice, and detecting their presence in human urines and plasmas upon kava intake. As expected, the abundances of these kavalactones differed significantly in kava products. All of them exhibited a large volume of distribution with extensive tissue affinity and adequate mean residence time (MRT) in mice. This method also successfully quantified these kavalactones in human body fluids upon kava consumption at the recommended human dose. This UPLC-MS/MS method therefore can be used to characterize kava products and its pharmacokinetics in animals and in humans.
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pilot in vivo structure activity relationship of Dihydromethysticin in blocking 4 methylnitrosamino 1 3 pyridyl 1 butanone induced o6 methylguanine and lung tumor in a j mice
Journal of Medicinal Chemistry, 2017Co-Authors: Manohar Puppala, Sreekanth C Narayanapillai, Pablo Leitzman, Pramod Upadhyaya, Gerard M Osullivan, Stephen S Hecht, Chengguo XingAbstract:(+)-Dihydromethysticin was recently identified as a promising lung cancer chemopreventive agent, while (+)-dihydrokavain was completely ineffective. A pilot in vivo structure–activity relationship (SAR) was explored, evaluating the efficacy of its analogs in blocking 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-induced short-term O6-methylguanine and long-term adenoma formation in the lung tissues in A/J mice. Both results revealed cohesive SARs, demonstrating that the methylenedioxy functional group in DHM is essential while the lactone functional group tolerates modifications.
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Pilot in Vivo Structure–Activity Relationship of Dihydromethysticin in Blocking 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone-Induced O6-Methylguanine and Lung Tumor in A/J Mice
Journal of Medicinal Chemistry, 2017Co-Authors: Manohar Puppala, Sreekanth C Narayanapillai, Pablo Leitzman, Pramod Upadhyaya, Stephen S Hecht, M. Gerard O'sullivan, Chengguo XingAbstract:(+)-Dihydromethysticin was recently identified as a promising lung cancer chemopreventive agent, while (+)-dihydrokavain was completely ineffective. A pilot in vivo structure–activity relationship (SAR) was explored, evaluating the efficacy of its analogs in blocking 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-induced short-term O6-methylguanine and long-term adenoma formation in the lung tissues in A/J mice. Both results revealed cohesive SARs, demonstrating that the methylenedioxy functional group in DHM is essential while the lactone functional group tolerates modifications.
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Dihydromethysticin dhm blocks tobacco carcinogen 4 methylnitrosamino 1 3 pyridyl 1 butanone nnk induced o6 methylguanine in a manner independent of the aryl hydrocarbon receptor ahr pathway in c57bl 6 female mice
Chemical Research in Toxicology, 2016Co-Authors: Sreekanth C Narayanapillai, Pablo Leitzman, Pramod Upadhyaya, Chengguo Xing, Carolyn J BagloleAbstract:4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is a key carcinogen responsible for tobacco smoke-induced lung carcinogenesis. Among the types of DNA damage caused by NNK and its metabolite, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), O6-methylguanine (O6-mG) is likely the most carcinogen in A/J mice. Results of our previous studies showed that levels of O6-mG and other types of NNAL-derived DNA damage were preferentially reduced in the lung of female A/J mice upon dietary treatment with Dihydromethysticin (DHM), a promising lung cancer chemopreventive agent from kava. Such a differential blockage may be mediated via an increased level of NNAL glucuronidation, thereby leading to its detoxification. The potential of the aryl hydrocarbon receptor (AhR) as an upstream target of DHM mediating these events was evaluated herein using Ahr+/– and Ahr–/– C57BL/6 female mice because DHM was reported as an AhR agonist. DHM (0.05, 0.2, and 1.0 mg/g of diet) and dihydrokavain (DHK, an inactive analogue,...
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dietary Dihydromethysticin increases glucuronidation of 4 methylnitrosamino 1 3 pyridyl 1 butanol in a j mice potentially enhancing its detoxification
Drug Metabolism and Disposition, 2016Co-Authors: Sreekanth C Narayanapillai, Pablo Leitzman, Pramod Upadhyaya, Stephen S Hecht, Linda B Von Weymarn, Steven G Carmella, Jordan Paladino, Sharon E Murphy, Chengguo XingAbstract:Effective chemopreventive agents are needed against lung cancer, the leading cause of cancer death. Results from our previous work showed that dietary Dihydromethysticin (DHM) effectively blocked initiation of lung tumorigenesis by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in A/J mice, and it preferentially reduced 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL)-derived DNA adducts in lung. This study explored the mechanism(s) responsible for DHM’s differential effects on NNK/NNAL-derived DNA damage by quantifying their metabolites in A/J mice. The results showed that dietary DHM had no effect on NNK or NNAL abundance in vivo, indicating that DHM does not affect NNAL formation from NNK. DHM had a minimal effect on cytochrome P450 2A5 (CYP2A5, which catalyzes NNK and NNAL bioactivation in A/J mouse lung), suggesting that it does not inhibit NNAL bioactivation. Dietary DHM significantly increased O-glucuronidated NNAL (NNAL-O-gluc) in A/J mice. Lung and liver microsomes from dietary DHM-treated mice showed enhanced activities for NNAL O-glucuronidation. These results overall support the notion that dietary DHM treatment increases NNAL detoxification, potentially accounting for its chemopreventive efficacy against NNK-induced lung tumorigenesis in A/J mice. The ratio of urinary NNAL-O-gluc and free NNAL may serve as a biomarker to facilitate the clinical evaluation of DHM-based lung cancer chemopreventive agents.
Sreekanth C Narayanapillai - One of the best experts on this subject based on the ideXlab platform.
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pilot in vivo structure activity relationship of Dihydromethysticin in blocking 4 methylnitrosamino 1 3 pyridyl 1 butanone induced o6 methylguanine and lung tumor in a j mice
Journal of Medicinal Chemistry, 2017Co-Authors: Manohar Puppala, Sreekanth C Narayanapillai, Pablo Leitzman, Pramod Upadhyaya, Gerard M Osullivan, Stephen S Hecht, Chengguo XingAbstract:(+)-Dihydromethysticin was recently identified as a promising lung cancer chemopreventive agent, while (+)-dihydrokavain was completely ineffective. A pilot in vivo structure–activity relationship (SAR) was explored, evaluating the efficacy of its analogs in blocking 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-induced short-term O6-methylguanine and long-term adenoma formation in the lung tissues in A/J mice. Both results revealed cohesive SARs, demonstrating that the methylenedioxy functional group in DHM is essential while the lactone functional group tolerates modifications.
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Pilot in Vivo Structure–Activity Relationship of Dihydromethysticin in Blocking 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone-Induced O6-Methylguanine and Lung Tumor in A/J Mice
Journal of Medicinal Chemistry, 2017Co-Authors: Manohar Puppala, Sreekanth C Narayanapillai, Pablo Leitzman, Pramod Upadhyaya, Stephen S Hecht, M. Gerard O'sullivan, Chengguo XingAbstract:(+)-Dihydromethysticin was recently identified as a promising lung cancer chemopreventive agent, while (+)-dihydrokavain was completely ineffective. A pilot in vivo structure–activity relationship (SAR) was explored, evaluating the efficacy of its analogs in blocking 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-induced short-term O6-methylguanine and long-term adenoma formation in the lung tissues in A/J mice. Both results revealed cohesive SARs, demonstrating that the methylenedioxy functional group in DHM is essential while the lactone functional group tolerates modifications.
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Dihydromethysticin dhm blocks tobacco carcinogen 4 methylnitrosamino 1 3 pyridyl 1 butanone nnk induced o6 methylguanine in a manner independent of the aryl hydrocarbon receptor ahr pathway in c57bl 6 female mice
Chemical Research in Toxicology, 2016Co-Authors: Sreekanth C Narayanapillai, Pablo Leitzman, Pramod Upadhyaya, Chengguo Xing, Carolyn J BagloleAbstract:4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is a key carcinogen responsible for tobacco smoke-induced lung carcinogenesis. Among the types of DNA damage caused by NNK and its metabolite, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), O6-methylguanine (O6-mG) is likely the most carcinogen in A/J mice. Results of our previous studies showed that levels of O6-mG and other types of NNAL-derived DNA damage were preferentially reduced in the lung of female A/J mice upon dietary treatment with Dihydromethysticin (DHM), a promising lung cancer chemopreventive agent from kava. Such a differential blockage may be mediated via an increased level of NNAL glucuronidation, thereby leading to its detoxification. The potential of the aryl hydrocarbon receptor (AhR) as an upstream target of DHM mediating these events was evaluated herein using Ahr+/– and Ahr–/– C57BL/6 female mice because DHM was reported as an AhR agonist. DHM (0.05, 0.2, and 1.0 mg/g of diet) and dihydrokavain (DHK, an inactive analogue,...
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dietary Dihydromethysticin increases glucuronidation of 4 methylnitrosamino 1 3 pyridyl 1 butanol in a j mice potentially enhancing its detoxification
Drug Metabolism and Disposition, 2016Co-Authors: Sreekanth C Narayanapillai, Pablo Leitzman, Pramod Upadhyaya, Stephen S Hecht, Linda B Von Weymarn, Steven G Carmella, Jordan Paladino, Sharon E Murphy, Chengguo XingAbstract:Effective chemopreventive agents are needed against lung cancer, the leading cause of cancer death. Results from our previous work showed that dietary Dihydromethysticin (DHM) effectively blocked initiation of lung tumorigenesis by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in A/J mice, and it preferentially reduced 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL)-derived DNA adducts in lung. This study explored the mechanism(s) responsible for DHM’s differential effects on NNK/NNAL-derived DNA damage by quantifying their metabolites in A/J mice. The results showed that dietary DHM had no effect on NNK or NNAL abundance in vivo, indicating that DHM does not affect NNAL formation from NNK. DHM had a minimal effect on cytochrome P450 2A5 (CYP2A5, which catalyzes NNK and NNAL bioactivation in A/J mouse lung), suggesting that it does not inhibit NNAL bioactivation. Dietary DHM significantly increased O-glucuronidated NNAL (NNAL-O-gluc) in A/J mice. Lung and liver microsomes from dietary DHM-treated mice showed enhanced activities for NNAL O-glucuronidation. These results overall support the notion that dietary DHM treatment increases NNAL detoxification, potentially accounting for its chemopreventive efficacy against NNK-induced lung tumorigenesis in A/J mice. The ratio of urinary NNAL-O-gluc and free NNAL may serve as a biomarker to facilitate the clinical evaluation of DHM-based lung cancer chemopreventive agents.
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Dietary Dihydromethysticin Increases Glucuronidation of 4-(Methylnitrosamino)-1-(3-Pyridyl)-1-Butanol in A/J Mice, Potentially Enhancing Its Detoxification.
Drug Metabolism and Disposition, 2016Co-Authors: Sreekanth C Narayanapillai, Pablo Leitzman, Pramod Upadhyaya, Stephen S Hecht, Linda B Von Weymarn, Steven G Carmella, Jordan Paladino, Sharon E Murphy, Chengguo XingAbstract:![Figure][1] Effective chemopreventive agents are needed against lung cancer, the leading cause of cancer death. Results from our previous work showed that dietary Dihydromethysticin (DHM) effectively blocked initiation of lung tumorigenesis by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in A/J mice, and it preferentially reduced 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL)-derived DNA adducts in lung. This study explored the mechanism(s) responsible for DHM’s differential effects on NNK/NNAL-derived DNA damage by quantifying their metabolites in A/J mice. The results showed that dietary DHM had no effect on NNK or NNAL abundance in vivo, indicating that DHM does not affect NNAL formation from NNK. DHM had a minimal effect on cytochrome P450 2A5 (CYP2A5, which catalyzes NNK and NNAL bioactivation in A/J mouse lung), suggesting that it does not inhibit NNAL bioactivation. Dietary DHM significantly increased O -glucuronidated NNAL (NNAL- O -gluc) in A/J mice. Lung and liver microsomes from dietary DHM-treated mice showed enhanced activities for NNAL O -glucuronidation. These results overall support the notion that dietary DHM treatment increases NNAL detoxification, potentially accounting for its chemopreventive efficacy against NNK-induced lung tumorigenesis in A/J mice. The ratio of urinary NNAL- O -gluc and free NNAL may serve as a biomarker to facilitate the clinical evaluation of DHM-based lung cancer chemopreventive agents. [1]: pending:yes
Pablo Leitzman - One of the best experts on this subject based on the ideXlab platform.
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pilot in vivo structure activity relationship of Dihydromethysticin in blocking 4 methylnitrosamino 1 3 pyridyl 1 butanone induced o6 methylguanine and lung tumor in a j mice
Journal of Medicinal Chemistry, 2017Co-Authors: Manohar Puppala, Sreekanth C Narayanapillai, Pablo Leitzman, Pramod Upadhyaya, Gerard M Osullivan, Stephen S Hecht, Chengguo XingAbstract:(+)-Dihydromethysticin was recently identified as a promising lung cancer chemopreventive agent, while (+)-dihydrokavain was completely ineffective. A pilot in vivo structure–activity relationship (SAR) was explored, evaluating the efficacy of its analogs in blocking 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-induced short-term O6-methylguanine and long-term adenoma formation in the lung tissues in A/J mice. Both results revealed cohesive SARs, demonstrating that the methylenedioxy functional group in DHM is essential while the lactone functional group tolerates modifications.
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Pilot in Vivo Structure–Activity Relationship of Dihydromethysticin in Blocking 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone-Induced O6-Methylguanine and Lung Tumor in A/J Mice
Journal of Medicinal Chemistry, 2017Co-Authors: Manohar Puppala, Sreekanth C Narayanapillai, Pablo Leitzman, Pramod Upadhyaya, Stephen S Hecht, M. Gerard O'sullivan, Chengguo XingAbstract:(+)-Dihydromethysticin was recently identified as a promising lung cancer chemopreventive agent, while (+)-dihydrokavain was completely ineffective. A pilot in vivo structure–activity relationship (SAR) was explored, evaluating the efficacy of its analogs in blocking 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-induced short-term O6-methylguanine and long-term adenoma formation in the lung tissues in A/J mice. Both results revealed cohesive SARs, demonstrating that the methylenedioxy functional group in DHM is essential while the lactone functional group tolerates modifications.
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Dihydromethysticin dhm blocks tobacco carcinogen 4 methylnitrosamino 1 3 pyridyl 1 butanone nnk induced o6 methylguanine in a manner independent of the aryl hydrocarbon receptor ahr pathway in c57bl 6 female mice
Chemical Research in Toxicology, 2016Co-Authors: Sreekanth C Narayanapillai, Pablo Leitzman, Pramod Upadhyaya, Chengguo Xing, Carolyn J BagloleAbstract:4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is a key carcinogen responsible for tobacco smoke-induced lung carcinogenesis. Among the types of DNA damage caused by NNK and its metabolite, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), O6-methylguanine (O6-mG) is likely the most carcinogen in A/J mice. Results of our previous studies showed that levels of O6-mG and other types of NNAL-derived DNA damage were preferentially reduced in the lung of female A/J mice upon dietary treatment with Dihydromethysticin (DHM), a promising lung cancer chemopreventive agent from kava. Such a differential blockage may be mediated via an increased level of NNAL glucuronidation, thereby leading to its detoxification. The potential of the aryl hydrocarbon receptor (AhR) as an upstream target of DHM mediating these events was evaluated herein using Ahr+/– and Ahr–/– C57BL/6 female mice because DHM was reported as an AhR agonist. DHM (0.05, 0.2, and 1.0 mg/g of diet) and dihydrokavain (DHK, an inactive analogue,...
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dietary Dihydromethysticin increases glucuronidation of 4 methylnitrosamino 1 3 pyridyl 1 butanol in a j mice potentially enhancing its detoxification
Drug Metabolism and Disposition, 2016Co-Authors: Sreekanth C Narayanapillai, Pablo Leitzman, Pramod Upadhyaya, Stephen S Hecht, Linda B Von Weymarn, Steven G Carmella, Jordan Paladino, Sharon E Murphy, Chengguo XingAbstract:Effective chemopreventive agents are needed against lung cancer, the leading cause of cancer death. Results from our previous work showed that dietary Dihydromethysticin (DHM) effectively blocked initiation of lung tumorigenesis by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in A/J mice, and it preferentially reduced 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL)-derived DNA adducts in lung. This study explored the mechanism(s) responsible for DHM’s differential effects on NNK/NNAL-derived DNA damage by quantifying their metabolites in A/J mice. The results showed that dietary DHM had no effect on NNK or NNAL abundance in vivo, indicating that DHM does not affect NNAL formation from NNK. DHM had a minimal effect on cytochrome P450 2A5 (CYP2A5, which catalyzes NNK and NNAL bioactivation in A/J mouse lung), suggesting that it does not inhibit NNAL bioactivation. Dietary DHM significantly increased O-glucuronidated NNAL (NNAL-O-gluc) in A/J mice. Lung and liver microsomes from dietary DHM-treated mice showed enhanced activities for NNAL O-glucuronidation. These results overall support the notion that dietary DHM treatment increases NNAL detoxification, potentially accounting for its chemopreventive efficacy against NNK-induced lung tumorigenesis in A/J mice. The ratio of urinary NNAL-O-gluc and free NNAL may serve as a biomarker to facilitate the clinical evaluation of DHM-based lung cancer chemopreventive agents.
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Dietary Dihydromethysticin Increases Glucuronidation of 4-(Methylnitrosamino)-1-(3-Pyridyl)-1-Butanol in A/J Mice, Potentially Enhancing Its Detoxification.
Drug Metabolism and Disposition, 2016Co-Authors: Sreekanth C Narayanapillai, Pablo Leitzman, Pramod Upadhyaya, Stephen S Hecht, Linda B Von Weymarn, Steven G Carmella, Jordan Paladino, Sharon E Murphy, Chengguo XingAbstract:![Figure][1] Effective chemopreventive agents are needed against lung cancer, the leading cause of cancer death. Results from our previous work showed that dietary Dihydromethysticin (DHM) effectively blocked initiation of lung tumorigenesis by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in A/J mice, and it preferentially reduced 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL)-derived DNA adducts in lung. This study explored the mechanism(s) responsible for DHM’s differential effects on NNK/NNAL-derived DNA damage by quantifying their metabolites in A/J mice. The results showed that dietary DHM had no effect on NNK or NNAL abundance in vivo, indicating that DHM does not affect NNAL formation from NNK. DHM had a minimal effect on cytochrome P450 2A5 (CYP2A5, which catalyzes NNK and NNAL bioactivation in A/J mouse lung), suggesting that it does not inhibit NNAL bioactivation. Dietary DHM significantly increased O -glucuronidated NNAL (NNAL- O -gluc) in A/J mice. Lung and liver microsomes from dietary DHM-treated mice showed enhanced activities for NNAL O -glucuronidation. These results overall support the notion that dietary DHM treatment increases NNAL detoxification, potentially accounting for its chemopreventive efficacy against NNK-induced lung tumorigenesis in A/J mice. The ratio of urinary NNAL- O -gluc and free NNAL may serve as a biomarker to facilitate the clinical evaluation of DHM-based lung cancer chemopreventive agents. [1]: pending:yes
Pramod Upadhyaya - One of the best experts on this subject based on the ideXlab platform.
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pilot in vivo structure activity relationship of Dihydromethysticin in blocking 4 methylnitrosamino 1 3 pyridyl 1 butanone induced o6 methylguanine and lung tumor in a j mice
Journal of Medicinal Chemistry, 2017Co-Authors: Manohar Puppala, Sreekanth C Narayanapillai, Pablo Leitzman, Pramod Upadhyaya, Gerard M Osullivan, Stephen S Hecht, Chengguo XingAbstract:(+)-Dihydromethysticin was recently identified as a promising lung cancer chemopreventive agent, while (+)-dihydrokavain was completely ineffective. A pilot in vivo structure–activity relationship (SAR) was explored, evaluating the efficacy of its analogs in blocking 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-induced short-term O6-methylguanine and long-term adenoma formation in the lung tissues in A/J mice. Both results revealed cohesive SARs, demonstrating that the methylenedioxy functional group in DHM is essential while the lactone functional group tolerates modifications.
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Pilot in Vivo Structure–Activity Relationship of Dihydromethysticin in Blocking 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone-Induced O6-Methylguanine and Lung Tumor in A/J Mice
Journal of Medicinal Chemistry, 2017Co-Authors: Manohar Puppala, Sreekanth C Narayanapillai, Pablo Leitzman, Pramod Upadhyaya, Stephen S Hecht, M. Gerard O'sullivan, Chengguo XingAbstract:(+)-Dihydromethysticin was recently identified as a promising lung cancer chemopreventive agent, while (+)-dihydrokavain was completely ineffective. A pilot in vivo structure–activity relationship (SAR) was explored, evaluating the efficacy of its analogs in blocking 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-induced short-term O6-methylguanine and long-term adenoma formation in the lung tissues in A/J mice. Both results revealed cohesive SARs, demonstrating that the methylenedioxy functional group in DHM is essential while the lactone functional group tolerates modifications.
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Dihydromethysticin dhm blocks tobacco carcinogen 4 methylnitrosamino 1 3 pyridyl 1 butanone nnk induced o6 methylguanine in a manner independent of the aryl hydrocarbon receptor ahr pathway in c57bl 6 female mice
Chemical Research in Toxicology, 2016Co-Authors: Sreekanth C Narayanapillai, Pablo Leitzman, Pramod Upadhyaya, Chengguo Xing, Carolyn J BagloleAbstract:4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is a key carcinogen responsible for tobacco smoke-induced lung carcinogenesis. Among the types of DNA damage caused by NNK and its metabolite, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), O6-methylguanine (O6-mG) is likely the most carcinogen in A/J mice. Results of our previous studies showed that levels of O6-mG and other types of NNAL-derived DNA damage were preferentially reduced in the lung of female A/J mice upon dietary treatment with Dihydromethysticin (DHM), a promising lung cancer chemopreventive agent from kava. Such a differential blockage may be mediated via an increased level of NNAL glucuronidation, thereby leading to its detoxification. The potential of the aryl hydrocarbon receptor (AhR) as an upstream target of DHM mediating these events was evaluated herein using Ahr+/– and Ahr–/– C57BL/6 female mice because DHM was reported as an AhR agonist. DHM (0.05, 0.2, and 1.0 mg/g of diet) and dihydrokavain (DHK, an inactive analogue,...
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dietary Dihydromethysticin increases glucuronidation of 4 methylnitrosamino 1 3 pyridyl 1 butanol in a j mice potentially enhancing its detoxification
Drug Metabolism and Disposition, 2016Co-Authors: Sreekanth C Narayanapillai, Pablo Leitzman, Pramod Upadhyaya, Stephen S Hecht, Linda B Von Weymarn, Steven G Carmella, Jordan Paladino, Sharon E Murphy, Chengguo XingAbstract:Effective chemopreventive agents are needed against lung cancer, the leading cause of cancer death. Results from our previous work showed that dietary Dihydromethysticin (DHM) effectively blocked initiation of lung tumorigenesis by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in A/J mice, and it preferentially reduced 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL)-derived DNA adducts in lung. This study explored the mechanism(s) responsible for DHM’s differential effects on NNK/NNAL-derived DNA damage by quantifying their metabolites in A/J mice. The results showed that dietary DHM had no effect on NNK or NNAL abundance in vivo, indicating that DHM does not affect NNAL formation from NNK. DHM had a minimal effect on cytochrome P450 2A5 (CYP2A5, which catalyzes NNK and NNAL bioactivation in A/J mouse lung), suggesting that it does not inhibit NNAL bioactivation. Dietary DHM significantly increased O-glucuronidated NNAL (NNAL-O-gluc) in A/J mice. Lung and liver microsomes from dietary DHM-treated mice showed enhanced activities for NNAL O-glucuronidation. These results overall support the notion that dietary DHM treatment increases NNAL detoxification, potentially accounting for its chemopreventive efficacy against NNK-induced lung tumorigenesis in A/J mice. The ratio of urinary NNAL-O-gluc and free NNAL may serve as a biomarker to facilitate the clinical evaluation of DHM-based lung cancer chemopreventive agents.
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Dietary Dihydromethysticin Increases Glucuronidation of 4-(Methylnitrosamino)-1-(3-Pyridyl)-1-Butanol in A/J Mice, Potentially Enhancing Its Detoxification.
Drug Metabolism and Disposition, 2016Co-Authors: Sreekanth C Narayanapillai, Pablo Leitzman, Pramod Upadhyaya, Stephen S Hecht, Linda B Von Weymarn, Steven G Carmella, Jordan Paladino, Sharon E Murphy, Chengguo XingAbstract:![Figure][1] Effective chemopreventive agents are needed against lung cancer, the leading cause of cancer death. Results from our previous work showed that dietary Dihydromethysticin (DHM) effectively blocked initiation of lung tumorigenesis by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in A/J mice, and it preferentially reduced 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL)-derived DNA adducts in lung. This study explored the mechanism(s) responsible for DHM’s differential effects on NNK/NNAL-derived DNA damage by quantifying their metabolites in A/J mice. The results showed that dietary DHM had no effect on NNK or NNAL abundance in vivo, indicating that DHM does not affect NNAL formation from NNK. DHM had a minimal effect on cytochrome P450 2A5 (CYP2A5, which catalyzes NNK and NNAL bioactivation in A/J mouse lung), suggesting that it does not inhibit NNAL bioactivation. Dietary DHM significantly increased O -glucuronidated NNAL (NNAL- O -gluc) in A/J mice. Lung and liver microsomes from dietary DHM-treated mice showed enhanced activities for NNAL O -glucuronidation. These results overall support the notion that dietary DHM treatment increases NNAL detoxification, potentially accounting for its chemopreventive efficacy against NNK-induced lung tumorigenesis in A/J mice. The ratio of urinary NNAL- O -gluc and free NNAL may serve as a biomarker to facilitate the clinical evaluation of DHM-based lung cancer chemopreventive agents. [1]: pending:yes
Gerard M Osullivan - One of the best experts on this subject based on the ideXlab platform.
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pilot in vivo structure activity relationship of Dihydromethysticin in blocking 4 methylnitrosamino 1 3 pyridyl 1 butanone induced o6 methylguanine and lung tumor in a j mice
Journal of Medicinal Chemistry, 2017Co-Authors: Manohar Puppala, Sreekanth C Narayanapillai, Pablo Leitzman, Pramod Upadhyaya, Gerard M Osullivan, Stephen S Hecht, Chengguo XingAbstract:(+)-Dihydromethysticin was recently identified as a promising lung cancer chemopreventive agent, while (+)-dihydrokavain was completely ineffective. A pilot in vivo structure–activity relationship (SAR) was explored, evaluating the efficacy of its analogs in blocking 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-induced short-term O6-methylguanine and long-term adenoma formation in the lung tissues in A/J mice. Both results revealed cohesive SARs, demonstrating that the methylenedioxy functional group in DHM is essential while the lactone functional group tolerates modifications.
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flavokawains a and b in kava not Dihydromethysticin potentiate acetaminophen induced hepatotoxicity in c57bl 6 mice
Chemical Research in Toxicology, 2014Co-Authors: Sreekanth C Narayanapillai, Pablo Leitzman, Gerard M Osullivan, Chengguo XingAbstract:Anxiolytic kava products have been associated with rare but severe hepatotoxicity in humans. This adverse potential has never been captured in animal models, and the responsible compound(s) remains to be determined. The lack of such knowledge greatly hinders the preparation of a safer kava product and limits its beneficial applications. In this study we evaluated the toxicity of kava as a single entity or in combination with acetaminophen (APAP) in C57BL/6 mice. Kava alone revealed no adverse effects for long-term usage even at a dose of 500 mg/kg bodyweight. On the contrary a three-day kava pretreatment potentiated APAP-induced hepatotoxicity, resulted in an increase in serum ALT and AST, and increased severity of liver lesions. Chalcone-based flavokawains A (FKA) and B (FKB) in kava recapitulated its hepatotoxic synergism with APAP while Dihydromethysticin (DHM, a representative kavalactone and a potential lung cancer chemopreventive agent) had no such effect. These results, for the first time, demonstr...
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Dihydromethysticin from kava blocks tobacco carcinogen 4 methylnitrosamino 1 3 pyridyl 1 butanone induced lung tumorigenesis and differentially reduces dna damage in a j mice
Carcinogenesis, 2014Co-Authors: Sreekanth C Narayanapillai, Pablo Leitzman, Pramod Upadhyaya, Gerard M Osullivan, Silvia Balbo, Alex E Grill, Ahmad Ali Shaik, Bo Zhou, Lisa A Peterson, Junxuan LuAbstract:We have previously shown that kava and its flavokavain-free Fraction B completely blocked 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced lung tumorigenesis in A/J mice with a preferential reduction in NNK-induced O 6-methylguanine (O 6-mG). In this study, we first identified natural (+)-Dihydromethysticin (DHM) as a lead compound through evaluating the in vivo efficacy of five major compounds in Fraction B on reducing O 6-mG in lung tissues. (+)-DHM demonstrated outstanding chemopreventive activity against NNK-induced lung tumorigenesis in A/J mice with 97% reduction of adenoma multiplicity at a dose of 0.05mg/g of diet (50 ppm). Synthetic (±)-DHM was equally effective as the natural (+)-DHM in these bioassays while a structurally similar analog, (+)-dihydrokavain (DHK), was completely inactive, revealing a sharp in vivo structure–activity relationship. Analyses of an expanded panel of NNK-induced DNA adducts revealed that DHM reduced a subset of DNA adducts in lung tissues derived from 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL, the active metabolite of NNK). Preliminary 17-week safety studies of DHM in A/J mice at a dose of 0.5mg/g of diet (at least 10× its minimum effective dose) revealed no adverse effects, suggesting that DHM is likely free of kava’s hepatotoxic risk. These results demonstrate the outstanding efficacy and promising safety margin of DHM in preventing NNK-induced lung tumorigenesis in A/J mice, with a unique mechanism of action and high target specificity.