Role of CYP2D6 gene polymorphism in individual's ability to quit smoking

Abstract

In 1980, we published two papers of importance for the future of our research: (i) it was shown that the two polymorphic hydroxylations of debrisoquine and sparteine are catalysed by a common enzyme now called CYP2D6 and (ii) that this polymorphic enzyme also catalysed the metabolism of the tricyclic antidepressant nortriptyline. Later, it was shown that most antidepressants are metabolized by CYP2D6. There are many allelic variants of CYP2D6 causing decreased (e.g. CYP2D6*10 in Asians) or no (*4 in Caucasians) activity of the enzyme. We have identified duplication and amplification of a CYP2D6 gene as a cause of ultrarapid metabolism. There are pronounced interethnic differences in these allelic variants. When nortriptyline was given as single doses to healthy subjects, there was a close relationship between the rate of 10-hydroxylation and the number of functional CYP2D6 genes.Most neuroleptic drugs are also metabolized by CYP2D6. Exceptions are the atypical neuroleptics clozapine and olanzapine, which are mainly metabolized by CYP1A2. When haloperidol was given as a single oral dose to a panel of healthy Swedish Caucasians, PM of debrisoquine eliminated the drug slower than EM (PM=poor, EM=extensive metabolisers). Among eight patients treated with i.m. injection of haloperidol decanoate every 4 weeks, one patient having the genotype CYP2D6*4/*4 and thus a PM, had the highest plasma concentration of haloperidol, highest dopamine D2-receptor occupancy and most pronounced extrapyramidal side-effects. In Japan, plasma concentrations of haloperidol per dose unit have been shown to be related to the CYP2D6*10 allele. In Koreans, this relationship was confirmed at doses of haloperidol below 20 mg per day, but not at higher doses. These and other studies taken together show that at low doses haloperidol is metabolized by CYP2D6, while at high doses, this enzyme is saturated and then enzymes with a higher capacity, e.g. CYP3A4, are taking over.CYP2D6 catalyzes the metabolism of a large number of psychotropic drugs and the pronounced variation in its activity between individuals and populations contributes to the variation in treatment response and side effects. Also, it must be emphasized that when two drugs, both of which are substrates of CYP2D6, are co-administrated they may increase each others' plasma concentrations and potentiate therapeutic effects and adverse drug reactions.