2. Academic Validation
  3. Dietary Dihydromethysticin Increases Glucuronidation of 4-(Methylnitrosamino)-1-(3-Pyridyl)-1-Butanol in A/J Mice, Potentially Enhancing Its Detoxification

Dietary Dihydromethysticin Increases Glucuronidation of 4-(Methylnitrosamino)-1-(3-Pyridyl)-1-Butanol in A/J Mice, Potentially Enhancing Its Detoxification

  • Drug Metab Dispos. 2016 Mar;44(3):422-7. doi: 10.1124/dmd.115.068387.
Sreekanth C Narayanapillai 1,  Linda B von Weymarn 1,  Steven G Carmella 1,  Pablo Leitzman 1,  Jordan Paladino 1,  Pramod Upadhyaya 1,  Stephen S Hecht 1,  Sharon E Murphy 1,  Chengguo Xing 2
Affiliations

Affiliations

  • 1 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.
  • 2 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.
PMID: 26744252 DOI: 10.1124/dmd.115.068387
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.

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