A method of regulating the activity of human cytochrome P450 isozyme CYP2A6 to
control nicotine metabolism or decrease the production of carcinogens from procarcinogens,
such as those present in tobacco smoke, in an individual by selectively inhibiting
CYP2A6. Various prophylactic (i.e., prevention and treatment) compositions and
methods are also described, including an improved oral nicotine composition and
method comprising the use of nicotine together with an inhibitor of the CYP2A6
enzyme. Furthermore, it has been discovered that the presence in an individual
of a mutant allele of human cytochrome P450 enzyme CYP2A6 (referred to throughout
this specification as "CYP2A6" for brevity) is predictive of an individual who:
(1) has a decreased risk of becoming a smoker, (ii) will smoke less if he/she becomes
dependent, and/or (iii) may be at relatively lower risk for cancer due to both
decreased smoke exposure and decreased CYP2A6 -mediated activation of tobacco smoke
and other procarcinogenic substrates. This invention provides diagnostic methods
for predicting tobacco dependence risk and risk for cancers related to CYP2A6 substrates
in an individual by analyzing for the presence of a mutant genotype for human cytochrome
P450 enzyme CYP2A6 in an individual, ranging from gene duplication (multiple copies
of CYP2A6) to single or even no copies due to null alleles or gene deletion.
