The essential role of the functional group in alkyl isothiocyanates for inhibition of tobacco nitrosamine-induced lung tumorigenesis |
| |
Authors: | Jiao, Ding Smith, Theresa J. Kim, Sungbin Yang, Chung S. Desai, Dhimant Amin, Shantu Chung, Fung-Lung |
| |
Affiliation: | Division of Chemical Carcinogenesis, Naylor Dana Institute for Disease Prevention, American Health Foundation Valhalla, NY 10595 1Laboratory for Cancer Research, College of Pharmacy, Rutgers University Piscataway, NY 08854, USA |
| |
Abstract: | The importance of the isothiocyanate group in alkyl isothiocyanatefor inhibition of tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone(NNK)-induced lung tumorigenesis was examined in A/J mice. Ourprevious structure-activity relationship study of isothiocyanatesshowed that 1-dodecyl isothiocyanate [CH3(CH2)11NCS], a simplealkyl isothiocyanate, is a potent inhibitor of NNK-induced lungtumorigenesis. It was chosenfor this study due to its structuralfeatures and potency. A single dose of 1-dodecyl isothiocyanategiven by gavage at 1 µmol/mouse 2 h prior to NNK administrationcompletely inhibited lung tumorigenesis, while removal of theisothiocyanate group or replacing it with a hydroxyl group abolishedthe inhibitory activity. These results demonstrate that theisothiocyanate functional group is critical for the inhibitoryactivity of isothiocyanates in NNK-induced lung tumorigenesis.To gain more insights into the relationship of in vivo inhibitionof tumorigenesis with the cytochrome P-450 enzyme inhibitoryactivity, the effects of these compounds on metabolism of NNKin mouse lung microsomes were studied. 1-Dodecyl isothiocyanateinhibited all three known oxidative pathways of NNK metabolism,with a stronger inhibitory activity toward NNK N-oxidation (IC50430 nM) and keto alcohol formation (IC50 500 nM) than keto aldehydeformation (IC50 13 000 nM). 1-Dodecanol had a similar selectivityin inhibition of these metabolic pathways, but was less potentthan 1-dodecyl isothiocyanate. Dodecane showed little or noinhibitory activity in the same concentration range. These resultsindicate that the isothiocyanate group of 1-dodecyl isothiocyanateis important for inhibition of NNK-induced lung tumorigenesisand also for effective inhibition of cytochrome P-450 enzymesinvolved in NNK oxidation. |
| |
Keywords: | |
本文献已被 Oxford 等数据库收录! |
|