CYP2D6

Cytochrome P450 2D6 (CYP2D6) is an enzyme that in humans is encoded by the CYP2D6 gene. CYP2D6 is primarily expressed in the liver. It is also highly expressed in areas of the central nervous system, including the substantia nigra. CYP2D6, a member of the cytochrome P450 mixed-function oxidase system, is one of the most important enzymes involved in the metabolism of xenobiotics in the body. In particular, CYP2D6 is responsible for the metabolism and elimination of approximately 25% of clinically used drugs, via the addition or removal of certain functional groups – specifically, hydroxylation, demethylation, and dealkylation. CYP2D6 also activates some prodrugs. This enzyme also metabolizes several endogenous substances, such as dimethyltryptamine, hydroxytryptamines, neurosteroids, and both m-tyramine and p-tyramine which CYP2D6 metabolizes into dopamine in the brain and liver. Considerable variation exists in the efficiency and amount of CYP2D6 enzyme produced between individuals. Hence, for drugs that are metabolized by CYP2D6 (that is, drugs that are CYP2D6 substrates), certain individuals will eliminate these drugs quickly (ultrarapid metabolizers) while others slowly (poor metabolizers). If a drug is metabolized quickly, the drug's efficacy may decrease, while if a drug is metabolized too slowly, toxicity may result. The dose of the drug may have to be adjusted to take into account of the speed at which it is metabolized by CYP2D6. People who more rapidly metabolize prodrugs, such as codeine or tramadol, reach higher-than-therapeutic levels. A case study of the death of an infant breastfed by an ultrarapid metabolizer mother taking codeine impacted postnatal pain relief clinical practices, but was later debunked. These drugs may also cause serious toxicity in ultrarapid metabolizer patients when used to treat other post-operative pain, such as after tonsillectomy. Other drugs may be inhibitors of CYP2D6 activity or inducers of CYP2D6 enzyme expression that will lead to decreased...