PT  - JOURNAL ARTICLE
AU  - Sreekanth C. Narayanapillai
AU  - Linda B. von Weymarn
AU  - Steven G. Carmella
AU  - Pablo Leitzman
AU  - Jordan Paladino
AU  - Pramod Upadhyaya
AU  - Stephen S. Hecht
AU  - Sharon E. Murphy
AU  - Chengguo Xing
TI  - Dietary Dihydromethysticin Increases Glucuronidation of 4-(Methylnitrosamino)-1-(3-Pyridyl)-1-Butanol in A/J Mice, Potentially Enhancing Its Detoxification
AID  - 10.1124/dmd.115.068387
DP  - 2016 Mar 01
TA  - Drug Metabolism and Disposition
PG  - 422--427
VI  - 44
IP  - 3
4099  - http://dmd.aspetjournals.org/content/44/3/422.short
4100  - http://dmd.aspetjournals.org/content/44/3/422.full
SO  - Drug Metab Dispos2016 Mar 01; 44
AB  - 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.