The potential role of the cytochrome P-450 2D6 pharmacogenetic polymorphism in drug abuse.

Cytochromes P-450 (P450s) are enzymes involved in the oxidative metabolism of a wide array of endogenous and exogenous molecules including steroids, plant metabolites, prostaglandins, biogenic amines, drugs, and chemical carcinogens. This broad spectrum of reactions is due to multiple P-450 isozymes with differing but overlapping substrate specificities. The mammalian P-450 superfamily consists of at least 12 families and over 400 individual genes (Nelson et al. 1993). Genetic variants of P-450 have been discovered because of atypical clinical responses in individuals who were subsequently shown to have a reduced ability to metabolize a drug. The most widely studied P-450 polymorphism was first revealed with the antihypertensive drug debrisoquin (Mahgoub et al. 1977). This drug is 4-hydroxylated by a P-450 enzyme called cytochrome P-450 2D6 (abbreviated CYP2D6) that is encoded by the CYP2D6 gene.