Identification of the primary gene defect at the cytochrome P₄₅₀ CYP2D locus

THE mammalian cytochrome P₄₅₀-dependent monooxygenase system is involved in the metabolism of drugs and chemical carcinogens^1-5. The role of these enzymes in toxicological response is exemplified by an autosomal recessive polymorphism at the cytochrome P₄₅₀ CYP2D6 debrisoquine hydroxylase locus which results in the severely compromised metabolism of at least 25 drugs, and which in some cases can lead to life-threatening side-effects^3,6-12. In addition, this polymorphism, which affects 8-10% of the caucasian population, has been associated with altered susceptibility to lung and bladder cancer^13-16. Here we report the identification of the primary mutation responsible for this metabolic defect and the development of a simple DNA-based genetic assay to allow both the identification of most individuals at risk of drug side-effects and clarification of the conflicting reports on the association of this polymorphism with cancer susceptibility^13-18.