Modifying the Metabolism of Nicotine as a Therapeutic Strategy

CYP2A6 is the enzyme responsible for the metabolic inactivation of around 90% of nicotine to cotinine. Individuals with genetically decreased CYP2A6 have slower rates of nicotine inactivation. We have found that slow nicotine inactivators are roughly twice less likely to be current adult smokers and those who are smoke 7–10 fewer cigarettes per day than people with normal metabolic rates. Slow nicotine inactivators also smoke for a shorter duration before quitting and may have increased success in quitting. Recently we have shown that imitating the protection offered by the slow metabolism, by inhibiting CYP2A6 activity in vivo, can decrease smoking. CYP2A6 is also involved in the activation of tobacco-smoke nitrosamines. Slow metabolizes are at lower risk for lung cancer and we have shown that CYP2A6 inhibitors can also decrease the nitrosamine activation (rerouting them to detoxified glucuronides). CYP2A6 inhibitors can be used alone, or with nicotine to make a nicotine oral pill, to inhibit the first-pass metabolism. CYP2A6 inhibitors can also increase nicotine plasma levels (and bioavailability) of nicotine when given with nicotine patch or gum. These approaches together may provide a better understanding of smoking behaviour and provide novel therapeutic approaches to smoking reduction and cessation.