Dihydromethysticin (DHM) Blocks Tobacco Carcinogen 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-Induced O6-Methylguanine in a Manner Independent of the Aryl Hydrocarbon Receptor (AhR) Pathway in C57BL/6 Female Mice

Sreekanth C. Narayanapillai, Shang Hsuan Lin, Pablo Leitzman, Pramod Upadhyaya, Carolyn J. Baglole, Chengguo Xing

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4 Scopus citations

Abstract

4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is a key carcinogen responsible for tobacco smoke-induced lung carcinogenesis. Among the types of DNA damage caused by NNK and its metabolite, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), O6-methylguanine (O6-mG) is likely the most carcinogen in A/J mice. Results of our previous studies showed that levels of O6-mG and other types of NNAL-derived DNA damage were preferentially reduced in the lung of female A/J mice upon dietary treatment with dihydromethysticin (DHM), a promising lung cancer chemopreventive agent from kava. Such a differential blockage may be mediated via an increased level of NNAL glucuronidation, thereby leading to its detoxification. The potential of the aryl hydrocarbon receptor (AhR) as an upstream target of DHM mediating these events was evaluated herein using Ahr+/- and Ahr-/- C57BL/6 female mice because DHM was reported as an AhR agonist. DHM (0.05, 0.2, and 1.0 mg/g of diet) and dihydrokavain (DHK, an inactive analogue, 1.0 mg/g of diet) were given to mice for 7 days, followed by a single intraperitoneal dose of NNK at 100 mg/kg of body weight. The effects of DHM on the amount of O6-mG in the lung, on the urinary ratio of glucuronidated NNAL (NNAL-Gluc) and free NNAL, and on CYP1A1/2 activity in the liver microsomes were analyzed. As observed in A/J mice, DHM treatment significantly and dose-dependently reduced the level of O6-mG in the target lung tissue, but there were no significant differences in O6-mG reduction between mice from Ahr+/- and Ahr-/- backgrounds. Similarly, in both strains, DHM at 1 mg/g of diet significantly increased the urinary ratio of NNAL-Gluc to free NNAL and CYP1A1/2 enzymatic activity in liver with no changes detected at lower DHM dosages. Because none of these effects of DHM were dependent on Ahr status, AhR clearly is not the upstream target for DHM.

Original languageEnglish (US)
Pages (from-to)1828-1834
Number of pages7
JournalChemical research in toxicology
Volume29
Issue number11
DOIs
StatePublished - Nov 21 2016

Bibliographical note

Funding Information:
This work was funded by Grant R01 CA 193278 (C.X.) from the National Cancer Institute of the National Institutes of Health, in part by National Cancer Institute Cancer Center Support Grant CA 077598, and by Canadian Institutes of Health Research (CIHR) Grant 123467 (C.J.B.). C.J.B. was supported by a salary award from the Fonds de recherche du Quebec-Sante (FRQ-S).

Publisher Copyright:
© 2016 American Chemical Society.

Copyright:
Copyright 2017 Elsevier B.V., All rights reserved.

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