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

Sreekanth C. Narayanapillai, Silvia Balbo, Pablo Leitzman, Alex E. Grill, Pramod Upadhyaya, Ahmad Ali Shaik, Bo Zhou, M. Gerard O'Sullivan, Lisa A. Peterson, Junxuan Lu, Stephen S. Hecht, Chengguo Xing

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Abstract

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 O6-methylguanine (O6-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 O6-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 0.05 mg/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 0.5 mg/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.

Original languageEnglish (US)
Pages (from-to)2365-2372
Number of pages8
JournalCarcinogenesis
Volume35
Issue number10
DOIs
StatePublished - Jan 1 2014

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Kava
Carcinogens
DNA Damage
Tobacco
Carcinogenesis
Lung
DNA Adducts
Diet
Safety
7,8-dihydromethysticin
4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone
Structure-Activity Relationship
Biological Assay
Adenoma

All Science Journal Classification (ASJC) codes

  • Cancer Research

Cite this

Narayanapillai, Sreekanth C. ; Balbo, Silvia ; Leitzman, Pablo ; Grill, Alex E. ; Upadhyaya, Pramod ; Shaik, Ahmad Ali ; Zhou, Bo ; Gerard O'Sullivan, M. ; Peterson, Lisa A. ; Lu, Junxuan ; Hecht, Stephen S. ; Xing, Chengguo. / 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. In: Carcinogenesis. 2014 ; Vol. 35, No. 10. pp. 2365-2372.
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abstract = "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 O6-methylguanine (O6-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 O6-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 0.05 mg/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 0.5 mg/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.",
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Narayanapillai, SC, Balbo, S, Leitzman, P, Grill, AE, Upadhyaya, P, Shaik, AA, Zhou, B, Gerard O'Sullivan, M, Peterson, LA, Lu, J, Hecht, SS & Xing, C 2014, '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, vol. 35, no. 10, pp. 2365-2372. https://doi.org/10.1093/carcin/bgu149

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. / Narayanapillai, Sreekanth C.; Balbo, Silvia; Leitzman, Pablo; Grill, Alex E.; Upadhyaya, Pramod; Shaik, Ahmad Ali; Zhou, Bo; Gerard O'Sullivan, M.; Peterson, Lisa A.; Lu, Junxuan; Hecht, Stephen S.; Xing, Chengguo.

In: Carcinogenesis, Vol. 35, No. 10, 01.01.2014, p. 2365-2372.

Research output: Contribution to journalArticle

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T1 - 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

AU - Narayanapillai, Sreekanth C.

AU - Balbo, Silvia

AU - Leitzman, Pablo

AU - Grill, Alex E.

AU - Upadhyaya, Pramod

AU - Shaik, Ahmad Ali

AU - Zhou, Bo

AU - Gerard O'Sullivan, M.

AU - Peterson, Lisa A.

AU - Lu, Junxuan

AU - Hecht, Stephen S.

AU - Xing, Chengguo

PY - 2014/1/1

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N2 - 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 O6-methylguanine (O6-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 O6-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 0.05 mg/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 0.5 mg/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.

AB - 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 O6-methylguanine (O6-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 O6-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 0.05 mg/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 0.5 mg/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.

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