Cytochrome P450 2D6.1 and cytochrome P450 2D6.10 differ in catalytic activity for multiple substrates

The CYP2D6 enzyme metabolizes many drugs, including antidepressants and amphetamines. A common variant, CYP2D6*10, found in about 75% of Asians, has Pro34Ser and Ser486Thr substitutions. In vitro tests using a baculovirus system showed that CYP2D6.10 has much lower intrinsic clearance than the wild-type CYP2D6.1 for several substrates: for dextromethorphan, the clearance ratio was 50; for MDMA, 123; for p-hydroxylation of methamphetamine, ratios ranged from 30 to 67; for N-demethylation, from 60 to 157, showing pathway and enantiomer selectivity. Inhibition susceptibility also varied: for debrisoquine, the Ki ratio was 8.1; for fluoxetine, 16; for norfluoxetine, 30. These findings suggest that individuals with CYP2D6*10/*10 may need different drug doses and have altered risks for toxicity, interactions, and amphetamine dependence compared to those with CYP2D6*1/*1.

Study at a glance

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.