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.

Autor:	Narayanapillai SC; Department of Medicinal Chemistry, College of Pharmacy and., Balbo S; Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA., Leitzman P; Department of Medicinal Chemistry, College of Pharmacy and., Grill AE; Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA., Upadhyaya P; Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA., Shaik AA; Department of Medicinal Chemistry, College of Pharmacy and Present address: Department of Chemistry, The University of Toledo, Toledo, OH 43606, USA., Zhou B; Department of Medicinal Chemistry, College of Pharmacy and., O'Sullivan MG; Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA, Department of Veterinary Population Medicine, University of Minnesota, St Paul, MN 55108, USA., Peterson LA; Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA, Division of Environmental Health Sciences, University of Minnesota, MN 55455, USA and., Lu J; Department of Biomedical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX 79106, USA., Hecht SS; Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA, xingx009@umn.edu hecht002@umn.edu., Xing C; Department of Medicinal Chemistry, College of Pharmacy and xingx009@umn.edu.
Jazyk:	angličtina
Zdroj:	Carcinogenesis [Carcinogenesis] 2014 Oct; Vol. 35 (10), pp. 2365-72. Date of Electronic Publication: 2014 Jul 22.
DOI:	10.1093/carcin/bgu149
Abstrakt:	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. (© The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)
Databáze:	MEDLINE
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