Mimicking gene defects to treat drug dependence.
The genetic basis for drug dependence has focused on genes that encode receptors involved in the reinforcing properties of drugs of abuse or that determine drug-taking behavior (e.g. impulsivity, etc.). Pharmacogenetic variations in the patterns of metabolism among individuals can also importantly modulate the risk of drug dependence. Cytochrome P450 drug metabolizing enzymes (CYPs), can activate (e.g. codeine to morphine) or deactivate (e.g. nicotine to cotinine) drugs of abuse. Some CYPs are polymorphic, that is, there are gene mutations which result in individuals with no (null mutations) or decreased enzyme activity (e.g. CYP2D6*10). Individuals with two null mutations appear in the population as phenotypic poor metabolizers. Using in vitro studies, we have identified drugs of abuse that are substrates of the polymorphic enzymes CYP2D6 (codeine, amphetamines, dextromethorphan), CYP2A6 (nicotine) and CYP2C19 (flunitrazepam). In human experimental studies, we have shown that CYP phenotype and genotype affect abuse liability of CYP2D6 metabolized drugs of abuse. In addition, we inhibited CYP2D6 and decreased individuals' risk of dependence experimentally (codeine, dextromethorphan) and treated codeine dependence. In epidemiologic studies CYP2D6 and CYP2A6 null mutations protect individuals from becoming codeine and tobacco dependent, respectively. With respect to CYP2A6, individuals with mutations, smoke fewer cigarettes and can quit more easily. Inhibiting CYP2A6 (e.g. tranylcypromine, methoxsalen) decreases smoking and the activation of procarcinogens. By mimicking these gene defects the risk of dependence can be decreased in individuals and new treatments developed.
Department of Pharmacology, University of Toronto, Ontario, Canada. e.sellers@utoronto.ca
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Sellers
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Tyndale
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases; D003061:Codeine / Q000378:metabolism; D065637:Cytochrome P-450 CYP2A6; D065731:Cytochrome P-450 CYP2C19; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics; D006801:Humans; D008694:Methamphetamine / Q000378:metabolism; D006899:Mixed Function Oxygenases / Q000235:genetics; D009538:Nicotine / Q000378:metabolism; D011110:Polymorphism, Genetic; D012907:Smoking / Q000009:adverse effects; D019966:Substance-Related Disorders / Q000188:drug therapy* / Q000209:etiology / Q000235:genetics
D008694:Methamphetamine; D009538:Nicotine; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C585710:CYP2A6 protein, human; C045793:CYP2C19 protein, human; D065637:Cytochrome P-450 CYP2A6; D065731:Cytochrome P-450 CYP2C19; D019389:Cytochrome P-450 CYP2D6; D003061:Codeine