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Research ArticleArticle

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

Sreekanth C. Narayanapillai, Linda B. von Weymarn, Steven G. Carmella, Pablo Leitzman, Jordan Paladino, Pramod Upadhyaya, Stephen S. Hecht, Sharon E. Murphy and Chengguo Xing
Drug Metabolism and Disposition March 2016, 44 (3) 422-427; DOI: https://doi.org/10.1124/dmd.115.068387
Sreekanth C. Narayanapillai
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
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Linda B. von Weymarn
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
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Steven G. Carmella
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
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Pablo Leitzman
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
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Jordan Paladino
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
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Pramod Upadhyaya
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
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Stephen S. Hecht
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
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Sharon E. Murphy
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
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Chengguo Xing
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
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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.

Footnotes

    • Received November 16, 2015.
    • Accepted January 6, 2016.
  • This work was supported by a grant from the National Institutes of Health National Cancer Institute [Grant R01 CA193278].

  • dx.doi.org/10.1124/dmd.115.068387.

  • Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 44 (3)
Drug Metabolism and Disposition
Vol. 44, Issue 3
1 Mar 2016
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Research ArticleArticle

Dihydromethysticin Increases NNAL-O-Glucuronidation In Vivo

Sreekanth C. Narayanapillai, Linda B. von Weymarn, Steven G. Carmella, Pablo Leitzman, Jordan Paladino, Pramod Upadhyaya, Stephen S. Hecht, Sharon E. Murphy and Chengguo Xing
Drug Metabolism and Disposition March 1, 2016, 44 (3) 422-427; DOI: https://doi.org/10.1124/dmd.115.068387

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Research ArticleArticle

Dihydromethysticin Increases NNAL-O-Glucuronidation In Vivo

Sreekanth C. Narayanapillai, Linda B. von Weymarn, Steven G. Carmella, Pablo Leitzman, Jordan Paladino, Pramod Upadhyaya, Stephen S. Hecht, Sharon E. Murphy and Chengguo Xing
Drug Metabolism and Disposition March 1, 2016, 44 (3) 422-427; DOI: https://doi.org/10.1124/dmd.115.068387
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