Oral Dosing of Dihydromethysticin Ahead of Tobacco Carcinogen NNK Effectively Prevents Lung Tumorigenesis in A/J Mice

Qi Hu, Pedro Corral, Sreekanth C. Narayanapillai, Pablo Leitzman, Pramod Upadhyaya, M. Gerard O'sullivan, Stephen S. Hecht, Junxuan Lu, Chengguo Xing

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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.

Original languageEnglish (US)
Pages (from-to)1980-1988
Number of pages9
JournalChemical research in toxicology
Issue number7
StatePublished - Jul 20 2020

Bibliographical note

Funding Information:
The research reported in this publication was supported in part by grants R01 CA193278 (CX), P01 CA138338 (Hecht), and R01 AT007395 (J.L., C.X.) from the National Institutes of Health, Frank Duckworth Endowment College of Pharmacy University of Florida (C.X.), and Startup Fund University of Florida Health Cancer Center (C.X.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or any funding agencies.

Publisher Copyright:
© 2020 American Chemical Society.

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't


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