Genetic variability in CYP3A4 and CYP3A5 in primary liver, gastric and colorectal cancer patients.
BACKGROUND
Drug-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.


METHODS
CYP3A4 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.


RESULTS
The 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.


CONCLUSIONS
Common polymorphisms on CYP3A4 and CYP3A5 genes do not modify the risk of developing digestive cancers in Western Europe.
Gervasini
Guillermo
G
Department of Pharmacology & Psychiatry, University of Extremadura, Badajoz, Spain. ggervasi@unex.es <ggervasi@unex.es>
García-Martín
Elena
E
Ladero
José M
JM
Pizarro
Rosa
R
Sastre
Javier
J
Martínez
Carmen
C
García
Monserrat
M
Diaz-Rubio
Manuel
M
Agúndez
José A G
JA
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D016022:Case-Control Studies; D016009:Chi-Square Distribution; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D012016:Reference Values; D012680:Sensitivity and Specificity; D013274:Stomach Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D016019:Survival Analysis
D003577:Cytochrome P-450 Enzyme System; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human