title: Functionally active duplications of the CYP2D6 gene are more prevalent among larynx and lung cancer patients.
abstract: The cytochrome P450 CYP2D6 is a polymorphic drug-metabolizing enzyme that is involved in the metabolism of several drugs and xenobiotics. Several independent studies indicate that the CYP2D6 metabolic status is a secondary factor in the risk of developing lung cancer, with individuals with high activity being at increased risk. The occurrence of functionally active duplications of the CYP2D6 gene is a phenomenon that affects 3-8% of Caucasians and up to 30% in some ethnic groups. These duplications cause ultrarapid metabolism of CYP2D6 substrates. In order to establish whether the highest CYP2D6 enzyme activity is associated with an increased risk of cancer, we analyzed the frequency of CYP2D6 gene duplications and enzyme-inactivating mutations in 199 Caucasian patients with lung or larynx cancer and in 335 healthy controls. A significantly increased frequency of carriers of the CYP2D6 gene duplication were found among lung and larynx cancer patients (13%), as compared with healthy controls (6.9%; p < 0.02). The frequency of the mutated active CYP2D6*9 allele was increased in lung cancer patients (p < 0.01) but not in larynx cancer patients. Global findings indicate that over 20% patients with lung or larynx cancer show CYP2D6 genotypes leading to ultrarapid metabolism or to the expression of an enzyme with altered kinetics (p < 0.01 vs. healthy controls). This may influence the metabolism of CYP2D6 substrates, including antineoplastic drugs and opioid derivatives used for pain relief in cancer patients. These patients would require higher doses than those considered as standard. We conclude that dosages for CYP2D6 substrates should be adapted to lung and larynx cancer patients.
authors.affiliation: Department of Pharmacology, Medical School, University of Extremadura, Badajoz, Spain.
authors.forename: J A
authors.initials: JA
authors.lastname: Agúndez
authors.forename: L
authors.initials: L
authors.lastname: Gallardo
authors.forename: M C
authors.initials: MC
authors.lastname: Ledesma
authors.forename: L
authors.initials: L
authors.lastname: Lozano
authors.forename: A
authors.initials: A
authors.lastname: Rodriguez-Lescure
authors.forename: J C
authors.initials: JC
authors.lastname: Pontes
authors.forename: M C
authors.initials: MC
authors.lastname: Iglesias-Moreno
authors.forename: J
authors.initials: J
authors.lastname: Poch
authors.forename: J M
authors.initials: JM
authors.lastname: Ladero
authors.forename: J
authors.initials: J
authors.lastname: Benítez
mesh_terms: D000328:Adult; D000368:Aged; D000483:Alleles; D000701:Analgesics, Opioid / Q000378:metabolism; D000970:Antineoplastic Agents / Q000378:metabolism; D016022:Case-Control Studies; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics* / Q000378:metabolism; D005260:Female; D020131:Genes, Duplicate; D006579:Heterozygote; D006801:Humans; D007822:Laryngeal Neoplasms / Q000150:complications / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics*; D008175:Lung Neoplasms / Q000150:complications / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D010146:Pain / Q000188:drug therapy / Q000209:etiology; D011110:Polymorphism, Genetic; D015995:Prevalence; D012907:Smoking / Q000009:adverse effects; D044465:White People / Q000235:genetics
chemical_list: D000701:Analgesics, Opioid; D000970:Antineoplastic Agents; D019389:Cytochrome P-450 CYP2D6