Functionally Active Duplications of the <i>CYP2D6</i> 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.

Two duplicated P450 genes are associated with pyrethroid resistance in Anopheles funestus, a major malaria vector

“…This is also supported by the observation made in Drosophila that both copies of CYP12D1 need to be overexpressed to confer a resistant phenotype (Daborn et al 2007). In humans, duplication of CYP2D6 results in an ultra-rapid metabolism of its substrates (Agundez et al 2001). Similarly, it is possible that the duplication of CYP6P9 and CYP6P4 increases pyrethroid metabolism in resistant An.…”

Identification of Novel Variants of the Flavin-Containing Monooxygenase Gene Family in African Americans

“…Interindividual variation in the activity of drug-metabolizing enzymes due to singlenucleotide substitutions, or insertions/deletions, is well documented (Hassett et al, 1994;Dolphin et al, 1997;Tang et al, 2001). In many cases, altered clinical responses or altered susceptibility to various chemicals due to these sequence variants have also been observed (Agundez et al, 2001). The nonsense mutations are highly likely to eliminate function and some of the 20 novel missense mutations may alter function.…”

“…This may be due to a change in the expression level, activity, or substrate specificity of the enzyme. P450 is the primary oxidative phase I pathway for the metabolism of drugs in humans, and certain polymorphisms in the CYP2D6 isoform are associated with adverse drug reactions (Agundez et al, 2001). Polymorphisms in phase II enzymes associated with adverse effects also have been described (Burchell and Hume, 1999).…”

Progress in the detection of human genome structural variations

“…The lower copy number of the CCL3L1 gene contributed to the enhanced susceptibility to HIV infection and progression to AIDS [62] . Dosage changes of cytochrome P450 genes such as CYP2D6 accounted for the variability in metabolism of tricyclic antidepressants and antipsychotic drugs, and were also related to laryngyal and lung cancers [63,64] , while homozygous deletions of the glutathione S-transferase genes (GSTT1 and GSTM1) gave rise to a higher risk of kinds of cancers [65] .…”