DESCRIPTION: (provided by Applicant) Genetic variations in genes involved in
the metabolic activation and/or detoxification of tobacco carcinogens are
likely to be a major source of inter-individual and inter-racial variation in
cancer susceptibility. These metabolic differences are often associated with
genetic polymorphisms in genes coding for carcinogen metabolizing enzymes.
Therefore, the carcinogenic capacity of tobacco and tobacco smoke may be
dependent upon the genetic composition of enzymes responsible for metabolizing
of these carcinogens, thereby affecting individual susceptibility to tobacco-
One of the important enzymes involved in the metabolism of major tobacco-smoke
carcinogens including | polycyclic aromatic hydrocarbons like benzo[a]pyrene
(BaP) is epoxide hydrolase (EH). The EH enzyme catalyzes the conversion of
BaP-(7,8)-epoxide to BaP-(7,8)-diol, which is the direct precursor metabolite
of BaP-(7,8)-diol-(9,10)-epoxide, the ultimate carcinogen of BaP. Previous
studies have implicated EH polymorphisms in increased risk for lung as well as
oral cancer in Caucasian cohorts but have not included an | assessment of EH
polymorphisms and cancer risk in other racial groups. We have established the
presence of other EH gene polymorphisms that could potentially play a role in
EH activity. As EH plays a key role in the activation of PAHs, a full
exploration of EH genetic variants must be performed and the role of
polymorphic EH alleles on EH activity.
Our hypothesis is that newly-identified EH genetic polymorphisms play an
important role in affecting enzyme activity. The goal of the present study is
to elucidate novel and examine known or newly-identified polymorphisms present
in the EH gene. In this proposal, we intend to examine the prevalence of
newly identified as well as known polymorphisms in Caucasians as well as
African Americans. In addition, we will examine the potential role of these
polymorphisms in EH activity by functional analysis of each allele. These
studies will provide baseline information for future large-scale case:control
studies regarding the potential of these polymorphisms to affect cancer risk
and influence our strategies in terms of cancer prevention for smoking-related
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