New method - HPB as surrogate Biomarker to NNN/NNK DNA adducts

 

N′-Nitrosonornicotine (NNN) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) are tobacco-specific nitrosamines (TSNAs). They occur in oral tobacco products including moist snuff, as well as in tobacco smoke. NNN and NNK can form DNA adducts, which are apperently responsible for their cancerogenic potential. Therefore, those TSNAs are classified to be ‘carcinogenic to humans’ (Class 1) by the IARC.  Briefly, metabolic activation of NNN and NNK give rise to a common reactive intermediate that forms adducts with haemoglobin and DNA, which upon hydrolysis lead to the release of 4-hydroxy-1-(3-pyridyl)-1-butanone (HPB) (see figure below). HPB-releasing adducts were reported to be more than 10 times higher in DNA of peripheral lung and tracheobronchial tissue of smokers as compared to nonsmokers. Adduct levels in lung and esophagus tissues were also found to be significantly higher in smokers who had lung cancer than in non-smokers suffering from the same disease.

 

Figure: Metabolism and formation of 4-hydroxy-1-(3-pyridyl)-1-butanone (HPB)-releasing adducts from NNK and NNN.

We developed and validated an ultra-sensitive UPLC-MS/MS method fro the determination of HPB released from DNA of various biological matrices. The method is characterized by an easy sample preparation procedure, short analysis time and low LOD (2 fmol/mg DNA).

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Max Scherer

Oct 23rd, 2014