Journal Article

The essential role of the functional group in alkyl isothiocyanates for inhibition of tobacco nitrosamine-induced lung tumorigenesis

Ding Jiao, Theresa J. Smith, Sungbin Kim, Chung S. Yang, Dhimant Desai, Shantu Amin and Fung-Lung Chung

in Carcinogenesis

Volume 17, issue 4, pages 755-759
Published in print April 1996 | ISSN: 0143-3334
Published online April 1996 | e-ISSN: 1460-2180 | DOI:
The essential role of the functional group in alkyl isothiocyanates
                    for inhibition of tobacco nitrosamine-induced lung tumorigenesis

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The importance of the isothiocyanate group in alkyl isothiocyanate for inhibition of tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced lung tumorigenesis was examined in A/J mice. Our previous structure-activity relationship study of isothiocyanates showed that 1-dodecyl isothiocyanate [CH3(CH2)11NCS], a simple alkyl isothiocyanate, is a potent inhibitor of NNK-induced lung tumorigenesis. It was chosenfor this study due to its structural features and potency. A single dose of 1-dodecyl isothiocyanate given by gavage at 1 μmol/mouse 2 h prior to NNK administration completely inhibited lung tumorigenesis, while removal of the isothiocyanate group or replacing it with a hydroxyl group abolished the inhibitory activity. These results demonstrate that the isothiocyanate functional group is critical for the inhibitory activity of isothiocyanates in NNK-induced lung tumorigenesis. To gain more insights into the relationship of in vivo inhibition of tumorigenesis with the cytochrome P-450 enzyme inhibitory activity, the effects of these compounds on metabolism of NNK in mouse lung microsomes were studied. 1-Dodecyl isothiocyanate inhibited all three known oxidative pathways of NNK metabolism, with a stronger inhibitory activity toward NNK N-oxidation (IC50 430 nM) and keto alcohol formation (IC50 500 nM) than keto aldehyde formation (IC50 13 000 nM). 1-Dodecanol had a similar selectivity in inhibition of these metabolic pathways, but was less potent than 1-dodecyl isothiocyanate. Dodecane showed little or no inhibitory activity in the same concentration range. These results indicate that the isothiocyanate group of 1-dodecyl isothiocyanate is important for inhibition of NNK-induced lung tumorigenesis and also for effective inhibition of cytochrome P-450 enzymes involved in NNK oxidation.

Journal Article.  0 words. 

Subjects: Clinical Cytogenetics and Molecular Genetics

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