title: 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.
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 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.
authors: Department of Medicinal Chemistry, College of Pharmacy and.
authors: Sreekanth C
authors: SC
authors: Narayanapillai
authors: Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA.
authors: Silvia
authors: S
authors: Balbo
authors: Department of Medicinal Chemistry, College of Pharmacy and.
authors: Pablo
authors: P
authors: Leitzman
authors: Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA.
authors: Alex E
authors: AE
authors: Grill
authors: Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA.
authors: Pramod
authors: P
authors: Upadhyaya
authors: Department of Medicinal Chemistry, College of Pharmacy and Present address: Department of Chemistry, The University of Toledo, Toledo, OH 43606, USA.
authors: Ahmad Ali
authors: AA
authors: Shaik
authors: Department of Medicinal Chemistry, College of Pharmacy and.
authors: Bo
authors: B
authors: Zhou
authors: Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA, Department of Veterinary Population Medicine, University of Minnesota, St Paul, MN 55108, USA.
authors: M Gerard
authors: MG
authors: O'Sullivan
authors: Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA, Division of Environmental Health Sciences, University of Minnesota, MN 55455, USA and.
authors: Lisa A
authors: LA
authors: Peterson
authors: Department of Biomedical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX 79106, USA.
authors: Junxuan
authors: J
authors: Lu
authors: Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA, xingx009@umn.edu hecht002@umn.edu.
authors: Stephen S
authors: SS
authors: Hecht
authors: Department of Medicinal Chemistry, College of Pharmacy and xingx009@umn.edu.
authors: Chengguo
authors: C
authors: Xing
mesh_terms: D000818:Animals; D002273:Carcinogens / Q000633:toxicity; D018736:DNA Adducts / Q000378:metabolism; D004249:DNA Damage / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006147:Guanine / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D020901:Kava / Q000737:chemistry*; D008099:Liver / Q000187:drug effects; D008175:Lung Neoplasms / Q000139:chemically induced / Q000517:prevention & control*; D051379:Mice; D008815:Mice, Inbred Strains; D009602:Nitrosamines / Q000633:toxicity*; D011753:Pyrones / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014026:Nicotiana / Q000737:chemistry
chemical_list: C107882:7,8-dihydromethysticin; D002273:Carcinogens; D018736:DNA Adducts; D009602:Nitrosamines; D011753:Pyrones; C113859:dihydrokavain; D006147:Guanine; C016583:4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone; C008449:O-(6)-methylguanine