Background and Aims: Hepatic enzyme CYP2E1 is involved in the
metabolism of a number of exogenous and endogenous substances
(i.e. ethanol, drugs and chemical carcinogens). Being polymorphic,
CYP2E1 gene can give different xeno-metabolic capabilities in a
population and it is well known that inadequate or no enzymatic
deactivation of xenobiotics could induce an increased susceptibility
to disease and cancer. In particular, one of the 5 -flanking region
polymorphisms, able to differentiate CYP2E1 gene transcriptional
activity, is caused by the appearance/disappearance of RsaI and
PstI restriction sites, which generates two different alleles, namely
*C1(Rsa+/Pst−) and *C2(Rsa−/Pst+) respectively, reported to be in
complete linkage disequilibrium.
Methods: To confirm the existence of a correlation between some
particular CYP2E1 genotypes/haplotypes and hepatocarcinoma, we
determined CYP2E1 PstI/RsaI genotypes/haplotypes by RFLP-PCR in
a cohort of central western Sicily hepatocarcinoma patients and in
a population of healthy students from the same geographic area.
Results: In hepatocarcinoma patients, modal genotype association
was Rsa++/Pst−−, corresponding to CYP2E1 *C1/*C1 haplotype,
whereas the Rsa+−/Pst−+ association, equivalent to CYP2E1 *C1/*C2
haplotype, resulted to have the lowest frequency both in patients
and in controls. Moreover, both in patients and in controls, noncanonical
genotype associations were frequent and arose from
a no-linkage disequilibrium between the two polymorphic sites.
Other authors reported this finding as a rare occurrence. Thus,
from analysis of only one restriction site, Rsa++ genotype was
approximately 1.5-fold more frequent in patients than in controls,
and the non-canonical Rsa+− genotype was found relatively
frequent in patients. Moreover, HuH7 and HA22T transformed
hepatocarcinoma cell lines also showed the Rsa+− genotype.
Conclusions: These results suggest that the presence in CYP2E1
genotype of at least one allele with an Rsa I restriction site is
correlated with hepatocarcinoma. As this site is known a consensus
sequence for some specific CYP gene transcription factors, like
HNF-1, it may be supposed that a single nucleotide polymorphism
can alter the possibility of HNF-1 to bind CYP2E1 promoter. This
could determine a marked change in the transcriptional activity
of the gene, incompetence in xenobiotic metabolism or in toxic
substance deactivation and an increased susceptibility to neoplastic
diseases, such as hepatocarcinoma
