Variable CYP2A6-mediated nicotine metabolism alters smoking behavior and risk

Nicotine is the psychoactive substance responsible for tobacco dependence; smokers adjust their cigarette consumption to maintain brain nicotine level s. In humans, 70 to 80% of nicotine is metabolized to the inactive metaboli te cotinine by the enzyme CYP2A6. CYP2A6 can also activate tobacco smoke pr ocarcinogens [e.g., NNK, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone]. I n initial studies we found that there was an under-representation of indivi duals carrying defective CYP2A6 alleles in a tobacco-dependent population, and that among smokers, those with deficient nicotine metabolism smoked few er cigarettes. We have since reproduced this data in a prospective smoking study (400 male and female, heavy and light smokers) examining the role of the CYP2A6 genotype on carbon monoxide levels, plasma and urine nicotine an d cotinine levels, and cigarette counts. We have also recently identified d eletion and duplication variants in the CYP2A6 gene locus and have examined their impact on smoking. These data provide the impetus to examine how inh ibition of CYP2A6 activity might be useful in a therapeutic context. Both k inetic and behavioral experiments in human smokers demonstrated that inhibi ting CYP2A6 in vivo decreased nicotine metabolism and smoking behavior. Thi s article summarizes the preliminary results from our studies.