ALLELIC VARIANTS OF CYP2E1 GENE IN HEPATOCARCINOMA PATIENTS AND IN HEPATIC TUMOR CELL LINES

Fabio Caradonna, Irene Catanzaro, Giuseppe Montalto, Lydia Giannitrapani, Flores Naselli, Antonio Mario Giacalone, Ignazio Demma, Marghereth Saverini

Risultato della ricerca: Posterpeer review

Abstract

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.
Lingua originaleEnglish
PagineS205-S205
Numero di pagine1
Stato di pubblicazionePublished - 2011

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