Functionally active duplications of the CYP2D6 gene are more prevalent among larynx and lung cancer patients

The cytochrome P-450 CYP2D6 is a polymorphic drug-metabolizing enzyme that is involved in the metabolism of several drugs and xenobiotics. Several ind ependent studies indicate that the CYP2D6 metabolic status is a secondary f actor in the risk of developing lung cancer, with individuals with high act ivity being at increased risk. The occurrence of functionally active duplic ations of the CYP2D6 gene is a phenomenon that affects 3-8% of Caucasians a nd up to 30% in some ethnic groups. These duplications cause ultrarapid met abolism of CYP2D6 substrates. In order to establish whether the highest CYP 2D6 enzyme activity is associated with an increased risk of cancer, we anal yzed the frequency of CYP2D6 gene duplications and enzyme-inactivating muta tions in 199 Caucasian patients with lung or larynx cancer and in 335 healt hy 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 muta ted 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 ultrar apid metabolism or to the expression of an enzyme with altered kinetics (p < 0.01 vs. healthy controls). This may influence the metabolism of CYP2D6 s ubstrates, including antineoplastic drugs and opioid derivatives used for p ain relief in cancer patients. These patients would require higher doses th an those considered as standard. We conclude that dosages for CYP2D6 substr ates should be adapted to lung and larynx cancer patients. Copyright (C) 20 01 S. Karger AG, Basel.