Abstract Of about one dozen human P450 s that catalyze biotransformations of xenobiotics, CYP2D6 is one of the more important ones based on the number of its drug sub- strates. It shows a very high degree of interindividual vari- ability, which is primarily due to the extensive genetic poly- morphism that influences expression and function. This so-called debrisoquine/sparteine oxidation polymorphism has been extensively studied in many different popula- tions and over 80 alleles and allele variants have been de- scribed. CYP2D6 protein and enzymatic activity is com- pletely absent in less than 1% of Asian people and in up to 10% of Caucasians with two null alleles, which do not en- code a functional P450 protein product. The resulting “poor metabolizer” (PM) phenotype is characterized by the in- ability to use CYP2D6-dependent metabolic pathways for drug elimination, which affect up to 20% of all clinically used drugs. The consequences are increased risk of ad- verse drug reactions or lack of therapeutic response. To- day, genetic testing predicts the PM phenotype with over 99% certainty. At the other extreme, the “Ultrarapid Me- tabolizer” (UM) phenotype can be caused by alleles car- rying multiple gene copies. “Intermediate Metabolizers” (IM) are severely deficient in their metabolism capacity compared to normal “Extensive Metabolizers” (EM), but in contrast to PMs they express a low amount of residual activity due to the presence of at least one partially defi- cient allele. Whereas the intricate genetics of the CYP2D6 polymorphism is becoming apparent at ever greater detail, applications in clinical practice are still rare. More clinical studies are needed to show where patients benefit from drug dose adjustment based on their genotype. Computational approaches are used to predict and rationalize substrate specificity and enzymatic properties of CYP2D6. Pharma- cophore modeling of ligands and protein homology mod- eling are two complementary approaches that have been applied with some success. CYP2D6 is not only expressed in liver but also in the gut and in brain neurons, where en- dogenous substrates with high-turnover have been found. Whether and how brain functions may be influenced by polymorphic expression are interesting questions for the future. Keywords Pharmacogenetics · Pharmacogenomics · Ultrarapid metabolizer · Intermediate metabolizer · Drug oxidation polymorphism · Cytochrome P450 · Drug metabolism Historical account of CYP2D6 discoveries In the 1970s, two research groups in England and in Ger- many observed that a few volunteers participating in phar- macokinetic studies with debrisoquine, a sympatholytic anti- hypertensive drug, and sparteine, an antiarrhythmic and oxy- tocic alkaloid drug, respectively, suffered from unexpected adverse reactions. In both cases the researchers showed that the affected individuals had a substantially impaired capacity to oxidize the drug and that the metabolic defect is under monogenic control and inherited as an autosomal recessive trait (Mahgoub et al. 1977; Eichelbaum et al. 1975, 1979). Soon later it was shown that both drug me- tabolism defects are phenotypes of the same genetic defi- ciency, i.e., PMs of debrisoquine are also PMs of sparteine and vice versa (Bertilsson et al. 1980; Eichelbaum et al. 1982). Other drugs were then found to be also inefficiently metabolized in PM individuals including metoprolol (Lennard et al. 1982), bufuralol (Dayer et al. 1982), and many others. A first attempt to rationalize structural require- ments and to predict CYP2D6 substrates was soon pre- sented (Wolff et al. 1985). The chemistry of the defective metabolic steps and early studies in human liver micro- somes had suggested the deficiency of a specific P450 en- zyme as cause of the PM phenotype (Kahn et al. 1982; Dayer et al. 1984). The enzyme was purified from solubi- lized human liver microsomes (Distlerath et al. 1985; Gut Ulrich M. Zanger · Sebastian Raimundo · Michel Eichelbaum Cytochrome P450 2D6: overview and update on pharmacology, genetics, biochemistry Naunyn-Schmiedeberg’s Arch Pharmacol (2004) 369 : 23–37 DOI 10.1007/s00210-003-0832-2 Received: 3 July 2003 / Accepted: 18 September 2003 / Published online: 15 November 2003 REVIEW U. M. Zanger (✉) · S. Raimundo · M. Eichelbaum Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Auerbachstrasse 112, 70376 Stuttgart, Germany Tel.: +49-711-81013704, Fax: +49-711-859295, e-mail: uli.zanger@ikp-stuttgart.de © Springer-Verlag 2003