title: Dietary Dihydromethysticin Increases Glucuronidation of 4-(Methylnitrosamino)-1-(3-Pyridyl)-1-Butanol in A/J Mice, Potentially Enhancing Its Detoxification.
abstract: 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.
authors.affiliation: Department of Medicinal Chemistry, College of Pharmacy (S.C.N., P.L., J.P., C.X.), Masonic Cancer Center (L.B.W., S.G.C., P.U., S.S.H., S.E.M.), and Department of Biochemistry, Molecular Biology and Biophysics (L.B.W., S.E.M.), University of Minnesota, Minneapolis, Minnesota.
authors.forename: Sreekanth C
authors.initials: SC
authors.lastname: Narayanapillai
authors.affiliation: Department of Medicinal Chemistry, College of Pharmacy (S.C.N., P.L., J.P., C.X.), Masonic Cancer Center (L.B.W., S.G.C., P.U., S.S.H., S.E.M.), and Department of Biochemistry, Molecular Biology and Biophysics (L.B.W., S.E.M.), University of Minnesota, Minneapolis, Minnesota.
authors.forename: Linda B
authors.initials: LB
authors.lastname: von Weymarn
authors.affiliation: Department of Medicinal Chemistry, College of Pharmacy (S.C.N., P.L., J.P., C.X.), Masonic Cancer Center (L.B.W., S.G.C., P.U., S.S.H., S.E.M.), and Department of Biochemistry, Molecular Biology and Biophysics (L.B.W., S.E.M.), University of Minnesota, Minneapolis, Minnesota.
authors.forename: Steven G
authors.initials: SG
authors.lastname: Carmella
authors.affiliation: Department of Medicinal Chemistry, College of Pharmacy (S.C.N., P.L., J.P., C.X.), Masonic Cancer Center (L.B.W., S.G.C., P.U., S.S.H., S.E.M.), and Department of Biochemistry, Molecular Biology and Biophysics (L.B.W., S.E.M.), University of Minnesota, Minneapolis, Minnesota.
authors.forename: Pablo
authors.initials: P
authors.lastname: Leitzman
authors.affiliation: Department of Medicinal Chemistry, College of Pharmacy (S.C.N., P.L., J.P., C.X.), Masonic Cancer Center (L.B.W., S.G.C., P.U., S.S.H., S.E.M.), and Department of Biochemistry, Molecular Biology and Biophysics (L.B.W., S.E.M.), University of Minnesota, Minneapolis, Minnesota.
authors.forename: Jordan
authors.initials: J
authors.lastname: Paladino
authors.affiliation: Department of Medicinal Chemistry, College of Pharmacy (S.C.N., P.L., J.P., C.X.), Masonic Cancer Center (L.B.W., S.G.C., P.U., S.S.H., S.E.M.), and Department of Biochemistry, Molecular Biology and Biophysics (L.B.W., S.E.M.), University of Minnesota, Minneapolis, Minnesota.
authors.forename: Pramod
authors.initials: P
authors.lastname: Upadhyaya
authors.affiliation: Department of Medicinal Chemistry, College of Pharmacy (S.C.N., P.L., J.P., C.X.), Masonic Cancer Center (L.B.W., S.G.C., P.U., S.S.H., S.E.M.), and Department of Biochemistry, Molecular Biology and Biophysics (L.B.W., S.E.M.), University of Minnesota, Minneapolis, Minnesota.
authors.forename: Stephen S
authors.initials: SS
authors.lastname: Hecht
authors.affiliation: Department of Medicinal Chemistry, College of Pharmacy (S.C.N., P.L., J.P., C.X.), Masonic Cancer Center (L.B.W., S.G.C., P.U., S.S.H., S.E.M.), and Department of Biochemistry, Molecular Biology and Biophysics (L.B.W., S.E.M.), University of Minnesota, Minneapolis, Minnesota.
authors.forename: Sharon E
authors.initials: SE
authors.lastname: Murphy
authors.affiliation: Department of Medicinal Chemistry, College of Pharmacy (S.C.N., P.L., J.P., C.X.), Masonic Cancer Center (L.B.W., S.G.C., P.U., S.S.H., S.E.M.), and Department of Biochemistry, Molecular Biology and Biophysics (L.B.W., S.E.M.), University of Minnesota, Minneapolis, Minnesota xingx009@umn.edu.
authors.forename: Chengguo
authors.initials: C
authors.lastname: Xing
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000187:drug effects; D018890:Chemoprevention / Q000379:methods; D018736:DNA Adducts / Q000187:drug effects; D004249:DNA Damage / Q000187:drug effects; D004032:Diet; D005260:Female; D008658:Inactivation, Metabolic / Q000187:drug effects*; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D008175:Lung Neoplasms / Q000378:metabolism / Q000517:prevention & control; D051379:Mice; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D009602:Nitrosamines / Q000378:metabolism*; D011753:Pyrones / Q000494:pharmacology*
chemical_list: C107882:7,8-dihydromethysticin; D018736:DNA Adducts; D009602:Nitrosamines; D011753:Pyrones; C016583:4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone