title: Association of CYP2C9 genotypes leading to high enzyme activity and colorectal cancer risk.
abstract: CYP2C9 enzyme activity is involved in the metabolism of substances related to colorectal cancer, and it is functionally linked to a genetic polymorphism. Two allelic variants of the CYP2C9 gene, namely CYP2C9*2 and CYP2C9*3, differ from wild-type CYP2C9*1 by single amino acid substitutions. These mutated alleles encode enzymes with altered properties that are associated with impaired metabolism. The present study evaluates the impact of CYP2C9 genotypes leading to high enzyme activity on colorectal cancer risk. For this, the frequency of allelic variants of the CYP2C9 gene was analysed in genomic DNA from 129 patients with colorectal cancer and in 150 healthy controls. Patients with colorectal cancer showed a statistically significant increase in the frequency of genotypes homozygous for the active CYP2C9*1 gene, as compared with healthy individuals. Such a high frequency is more significant among patients with cancer in proximal segments of the colon (P < 0.025; odds ratio 2.36 95% CI 1.18-4.72), and decreases in more distal tumour locations. We conclude that CYP2C9 polymorphism can be considered as a secondary risk factor for colorectal cancer in the studied population: those individuals with genotypes leading to high enzyme activity were at increased risk. The association of the CYP2C9 polymorphism to colorectal cancer risk could be related to CYP2C9-mediated metabolic activation of polycyclic aromatic hydrocarbons and heterocyclic aromatic amines. In addition, the key role of CYP2C9 in the metabolic inactivation of non-steroidal anti- inflammatory drugs could diminish the protective effect of these drugs against colorectal cancer.
authors.affiliation: Department of Pharmacology, Medical School, University of Extremadura, Avda. de Elvas s/n, E-06071, Badajoz, Spain.
authors.forename: C
authors.initials: C
authors.lastname: Martínez
authors.forename: E
authors.initials: E
authors.lastname: García-Martín
authors.forename: J M
authors.initials: JM
authors.lastname: Ladero
authors.forename: J
authors.initials: J
authors.lastname: Sastre
authors.forename: F
authors.initials: F
authors.lastname: Garcia-Gamito
authors.forename: M
authors.initials: M
authors.lastname: Diaz-Rubio
authors.forename: J A
authors.initials: JA
authors.lastname: Agúndez
mesh_terms: D000483:Alleles; D001189:Aryl Hydrocarbon Hydroxylases; D015179:Colorectal Neoplasms / Q000201:enzymology / Q000235:genetics*; D065729:Cytochrome P-450 CYP2C9; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D005838:Genotype; D006801:Humans; D039181:Steroid 16-alpha-Hydroxylase; D013250:Steroid Hydroxylases / Q000235:genetics*
chemical_list: D003577:Cytochrome P-450 Enzyme System; D013250:Steroid Hydroxylases; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; D039181:Steroid 16-alpha-Hydroxylase