title: Cytochrome P450 2D6.1 and cytochrome P450 2D6.10 differ in catalytic activity for multiple substrates.
abstract: CYP2D6 is involved in the metabolism of several classes of drugs, including tricyclic antidepressants, selective serotonin reuptake inhibitors and various amphetamines. CYP2D6*10 is an allelic variant, producing an enzyme with Pro34Ser and Ser486Thr amino acid substitutions. Approximately 75% of Asians possess the *10 allele. We sought to further characterize CYP2D6.10 catalytically in vitro in a baculovirus expression system using various substrates and inhibitors, in comparison to CYP2D6.1 (wild-type). Using dextromethorphan (DEX), P-methoxyamphetamine, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and (+/-)3,4-methylenedioxymethamphetamine (MDMA), the ratios of intrinsic clearance (Vmax/Km) of *1 to *10 were 50, 34, 22 and 123, respectively. The CYP2D6 substrates amitriptyline, and (+) and (-) methamphetamine (MAMP) are both p-hydroxylated and N-demethylated (NDM). The intrinsic clearance *1/*10 ratios were 42, 30 and 67 for the p-hydroxylation; and 60, 120 and 157 for the NDM, respectively, illustrating chemical pathway and enantiomeric selectivity for MAMP. It was apparent that (+) and (-) MAMP NDM and MDMA demethylenation were most significantly different in CYP2D6.10. Using DEX as the substrate, the ratios of Ki(*10)/Ki(*1) for inhibitors were: budipine (1.3), sparteine (1.6), debrisoquine (8.1), fluoxetine (16), norfluoxetine (30), paroxetine (14), MDMA (21) and MMDA-2 (7.1), indicating that CYP2D6.10 shows drug-specific altered susceptibility to inhibition. Taken together, these data suggest that CYP2D6*10/*10 individuals may be expected to require different drug doses; and show altered susceptibility to toxicity, interaction risk and, in the case of the amphetamines, drug dependence and toxicity compared to CYP2D6*1/*1 individuals.
authors.affiliation: Department of Pharmacology, University of Toronto, Toronto, Canada.
authors.forename: Y
authors.initials: Y
authors.lastname: Ramamoorthy
authors.forename: R F
authors.initials: RF
authors.lastname: Tyndale
authors.forename: E M
authors.initials: EM
authors.lastname: Sellers
mesh_terms: D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000378:metabolism; D000639:Amitriptyline / Q000378:metabolism; D000662:Amphetamines / Q000378:metabolism*; D000929:Antidepressive Agents, Tricyclic / Q000378:metabolism*; D019389:Cytochrome P-450 CYP2D6 / Q000378:metabolism*; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D017367:Selective Serotonin Reuptake Inhibitors / Q000378:metabolism*; D013379:Substrate Specificity
chemical_list: D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D000639:Amitriptyline; D000662:Amphetamines; D000929:Antidepressive Agents, Tricyclic; D019389:Cytochrome P-450 CYP2D6; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D007527:Isoenzymes; D017367:Selective Serotonin Reuptake Inhibitors