A previously unsuspected route of nicotine metabolism has been found, which has caused researchers in the United States to question the long-term safety of nicotine replacement preparations .
Dr Stephen Hecht and colleagues (University of Minnesota Cancer Centre) investigated the excretion pathway of two nicotine metabolites — a keto acid and a hydroxy acid. Keto and hydroxy acids make up 10 to 15 per cent of nicotine metabolites in smokers and nicotine patch users (the main metabolite of nicotine is cotinine) but they seem to be excreted via a hitherto unsuspected mechanism. This mechanism was thought only to exist in bacterial systems but, if it occurs in humans too, the keto and hydroxy acids might be metabolised into the aminoketone 4-(methylamino)-1-(3-pyridyl)-1-butanone. This is a precursor of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), a lung carcinogen, they say.
When the researchers incubated human liver microsomes with nicotine and cofactors, they found that the aminoketone was formed and then converted into a keto acid.
Although they did not find evidence of in vivo production of NNK, they say that it is a theoretical possibility that could result in smokers and nicotine replacement therapy users being exposed to the carcinogen.
Dr Hecht et al say: "Without question, nicotine replacement therapy is clearly preferable to continued use of tobacco products. "But they question the safety of nicotine products when used long-term. They add that they are now beginning research to confirm whether the aminoketone metabolite of nicotine is converted into NNK in the body (Proceedings of the National Academy of Sciences early edition, available at www.pnas.org).