Background and Aims: Hepatic enzyme CYP2E1 is involved in themetabolism 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 apopulation and it is well known that inadequate or no enzymaticdeactivation of xenobiotics could induce an increased susceptibilityto disease and cancer. In particular, one of the 5 -flanking regionpolymorphisms, able to differentiate CYP2E1 gene transcriptionalactivity, is caused by the appearance/disappearance of RsaI andPstI restriction sites, which generates two different alleles, namely*C1(Rsa+/Pst−) and *C2(Rsa−/Pst+) respectively, reported to be incomplete linkage disequilibrium.Methods: To confirm the existence of a correlation between someparticular CYP2E1 genotypes/haplotypes and hepatocarcinoma, wedetermined CYP2E1 PstI/RsaI genotypes/haplotypes by RFLP-PCR ina cohort of central western Sicily hepatocarcinoma patients and ina population of healthy students from the same geographic area.Results: In hepatocarcinoma patients, modal genotype associationwas Rsa++/Pst−−, corresponding to CYP2E1 *C1/*C1 haplotype,whereas the Rsa+−/Pst−+ association, equivalent to CYP2E1 *C1/*C2haplotype, resulted to have the lowest frequency both in patientsand in controls. Moreover, both in patients and in controls, noncanonicalgenotype associations were frequent and arose froma 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 wasapproximately 1.5-fold more frequent in patients than in controls,and the non-canonical Rsa+− genotype was found relativelyfrequent in patients. Moreover, HuH7 and HA22T transformedhepatocarcinoma cell lines also showed the Rsa+− genotype.Conclusions: These results suggest that the presence in CYP2E1genotype of at least one allele with an Rsa I restriction site iscorrelated with hepatocarcinoma. As this site is known a consensussequence for some specific CYP gene transcription factors, likeHNF-1, it may be supposed that a single nucleotide polymorphismcan alter the possibility of HNF-1 to bind CYP2E1 promoter. Thiscould determine a marked change in the transcriptional activityof the gene, incompetence in xenobiotic metabolism or in toxicsubstance deactivation and an increased susceptibility to neoplasticdiseases, such as hepatocarcinoma.
|Number of pages||1|
|Publication status||Published - 2011|