Abstract
BackgroundDrug-metabolizing enzymes play a role in chemical carcinogenesis through enzymatic activation of procarcinogens to biologically reactive metabolites. The role of gene polymorphisms of several cytochrome P450 enzymes in digestive cancer risk has been extensively investigated. However, the drug-metabolizing enzymes with the broader substrate specificity, CYP3A4 and CYP3A5, have not been analyzed so far. This study aims to examine associations between common CYP3A4 and CYP3A5 polymorphisms and digestive cancer risk.MethodsCYP3A4 and CYP3A5 genotypes were determined in 574 individuals including 178 patients with primary liver cancer, 82 patients with gastric cancer, 151 patients with colorectal cancer, and 163 healthy individuals.ResultsThe variant allele frequencies for patients with liver cancer, gastric cancer, colorectal cancer and healthy controls, respectively, were: CYP3A4*1B, 4.8 % (95% C.I. 2.6–7.0), 3.7 % (0.8–6.6) 4.3% (2.0–6.6) and 4.3% (2.1–6.5); CYP3A5*3, 91.8 % (93.0–97.4), 95.7% (92.6–98.8), 91.7% (88.6–94.8) and 90.8% (87.7–93.9). The association between CYP3A4*1B and CYP3A5*3 variant alleles did not significantly differ among patients and controls. No differences in genotypes, allele frequencies, or association between variant alleles were observed with regard to gender, age at diagnosis, tumour site or stage.ConclusionCommon polymorphisms on CYP3A4 and CYP3A5 genes do not modify the risk of developing digestive cancers in Western Europe.
Highlights
Drug-metabolizing enzymes play a role in chemical carcinogenesis through enzymatic activation of procarcinogens to biologically reactive metabolites
Seven different combinations of CYP3A4 and CYP3A5 genotypes were identified in the study groups
The allele frequencies for CYP3A5*3 were 91.9, 95.7, and 91.7% for liver, stomach and colorectal cancer patients, respectively, and 90.8% among healthy individuals
Summary
Drug-metabolizing enzymes play a role in chemical carcinogenesis through enzymatic activation of procarcinogens to biologically reactive metabolites. The identification of low penetrance genes able to increase the risk of developing cancer could constitute a major tool for the identification of individuals with inheritable altered susceptibility In this regard, the role of drug-metabolizing enzymes in cancer risk has been the (page number not for citation purposes). Several studies have focused on the role of gene polymorphisms or enzyme activities of CYP1A1 [5,6,7,8,9,10,11], CYP1A2 [7,12,13,14], CYP1B1 [7,15] and CYP2E1 [6,16,17,18,19] in digestive cancer risk. The impact on cancer risk of polymorphisms of the CYP enzymes with the broader substrate specificity, namely CYP3A4 and CYP3A5, has not been analyzed in detail so far
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